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Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Cordyceps  – Rare parasitic fungi could have anti-flammatory benefits


19 Nov 2012
Caterpillar fungi (Cordyceps) are rare parasites found on hibernating caterpillars in the mountains of Tibet. For centuries they have been highly prized as a traditional Chinese medicine – just a small amount can fetch hundreds of pounds.

Scientists at The University of Nottingham have been studying how this fungus could work by studying cordycepin, one of the drugs found in these mushrooms. They have already discovered that cordycepin has potential as a cancer drug. Their new work indicates that it could also have anti-inflammatory characteristics with the potential to help sufferers of asthma, rheumatoid arthritis, renal failure and stroke damage.

The research, published today in the academic journal RNA, was led by Dr Cornelia de Moor in the School of Pharmacy. It shows that cordycepin reduces inflammatory gene products in airway smooth muscle cells – the cells that contract during an asthma attack.

Several studies have suggested…

View original post 347 more words

Optimisation of Conditions for O-Benzyl and N-Benzyloxycarbonyl Protecting Group Removal using an Automated Flow Hydrogenator

Optimisation of Conditions for O-Benzyl and N-Benzyloxycarbonyl Protecting Group Removal using an Automated Flow Hydrogenator

K.R. Knudsen, J. Holden, S.V. Ley and M. Ladlow, Adv. Syn. Cat. 2007, 349, 535-538.

A versatile, fully automated flow hydrogenator has been developed that is able to perform sequential flow optimisation experiments, flow library hydrogenation, or iterative scale-up hydrogenation. The behaviour of a palladium catalyst in effecting removal of O-benzyl and N-benzyloxycarbonyl protecting groups has been investigated. Significant observations relating to maintaining optimal throughput are reported. A small library of peptidic derivatives has been deprotected in high yield and purity.


System configuration:
The system used was configured from a Gilson liquid handler (233XL), driven with a 10 mL
syringe pump (402). The syringe pump was connected to the sampling needle via a 2-way 6
position switching valve. This single channel liquid handler was used to perform both substrate
manipulation and fraction collection. The liquid handler was connected via a 2-way 6 position
injection valve to a Thales H-CubeTM flow hydrogenator driven with a KnauerTM A120 high
pressure pump. The collection vials were housed in specially designed gas tight blocks (2 x 7)
which were fitted with PTFA seals to enable penetration by the liquid handler needle, and
continuously purged with nitrogen in order to dilute and vent excess hydrogen safely. The
hardware was controlled using a single graphic user interface (HydroMateTM, Figure 2) which
utilised either RS232 or GSIOC connectivity to interface with the Thales and Gilson devices
respectively. Throughout 30 mm, 4 mm id 10% Pd/C catalyst cartridges (CatCartTM) were used
in conjunction with a 5 mL sample injection loop, although larger cartridges are also available.


The control software exploits software ‘wizards’ to assist the user in compiling a sequence of
optimisation experiments, or alternatively permits the implementation of a series of repetitive
experiments for either: (i) catalyst evaluation, (ii) reaction optimisation, (iii) compound library
synthesis, or (iv) as part of an automated, unattended scale up campaign (Figure 1). Experiments
may be devised with variations in scale, temperature, flow rate, and pressure in addition to
periodicity of fraction collection.
Analysis: RP-HPLC was run on a Hewlett Packard 1050 instrument. Column: Supelcosilä
PLUS column, 3.3 cm, 4.6 mm f, 3 mm. Eluent: A: water, 0.1% TFA, B: acetonitrile 95%,
water 5%, TFA 0.05%. Gradient: 10 to 95% B in A (1 mL min-1
) over 8 min. Detection: UV
(diode array detector).

A Microcapillary Flow Disc (MFD) Reactor for Organic Synthesis


A Microcapillary Flow Disc (MFD) Reactor for Organic Synthesis,

C.H. Hornung, M.R. Mackley, I.R. Baxendale and S.V. Ley and, Org. Proc. Res. Dev., 2007, 11, 399-405.

This paper reports proof of concept, development, and trials for a novel plastic microcapillary flow disc (MFD) reactor. The MFD was constructed from a flexible, plastic microcapillary film (MCF), comprising parallel capillary channels with diameters in the range of 80−250 μm. MCFs were wound into spirals and heat treated to form solid discs, which were then capable of carrying out continuous flow reactions at elevated temperatures and pressures and with a controlled residence time. Three reaction schemes were conducted in the system, namely the synthesis of oxazoles, the formation of an allyl-ether, and a Diels−Alder reaction. Reaction scales of up to four kilograms per day could be achieved. The potential benefits of the MFD technology are compared against those of other reactor geometries including both conventional lab-scale and other microscale devices.


Continuous Flow Ligand-Free Heck Reactions Using Monolithic Pd[0] Nanoclusters



Continuous Flow Ligand-Free Heck Reactions Using Monolithic Pd[0] Nanoclusters

N. Nikbin, M. Ladlow, S.V. Ley, Org. Proc. Res. Dev., 2007, 11, 458-462.



Flow-through reactor setup.

Abstract Image


An automated reactor has been developed for performing ligand-free Heck reactions in continuous flow mode. The reactor utilises a monolithic reactor cartridge derivatised with Pd(0) nanoparticles in-line with a scavenging cartridge containing Quadrapure-TU to efficiently capture palladium residues and thereby afford Heck products directly in high purity.





MK-966, MK-0966, Vioxx


Percent Composition: C 64.95%, H 4.49%, O 20.36%, S 10.20%
LitRef: Selective cyclooxygenase-2 (COX-2) inhibitor. Prepn: Y. Ducharme et al., WO 9500501; eidem, US5474995 (both 1995 to Merck Frosst).
Properties: White to off-white to light yellow powder. Sparingly sol in acetone; slightly sol in methanol, isopropyl acetate; very slightly sol in ethanol. Practically insol in octanol; insol in water.
Therap-Cat: Anti-inflammatory; analgesic.

Rofecoxib /ˌrɒfɨˈkɒksɪb/ is a nonsteroidal anti-inflammatory drug (NSAID) that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritisacute pain conditions, and dysmenorrhoea. Rofecoxib was approved by the Food and Drug Administration (FDA) on May 20, 1999, and was marketed under the brand names VioxxCeoxx, and Ceeoxx.

No Exclusivity found

Patent No Expirey Date patent use code
5474995 Jun 24, 2013 U-602
5474995*PED Dec 24, 2013
5691374 May 18, 2015
5691374*PED Nov 18, 2015
6063811 May 6, 2017 U-602
6063811*PED Nov 6, 2017
6239173 Jun 24, 2013 U-602
6239173*PED Dec 24, 2013



Systematic (IUPAC) name
Clinical data
Pregnancy cat. (AU)
Legal status Prescription Only (S4) (AU)withdrawn
Routes oral
Pharmacokinetic data
Bioavailability 93%
Protein binding 87%
Metabolism hepatic
Half-life 17 hours
Excretion biliary/renal
CAS number 162011-90-7 Yes
ATC code M01AH02
PubChem CID 5090
DrugBank DB00533
ChemSpider 4911 Yes
Chemical data
Formula C17H14O4S 
Mol. mass 314.357 g/mol

Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.[1]

On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib’s risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.[2] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[3] Merck reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens.

Rofecoxib was available on prescription in both tablet-form and as an oral suspension. It was available by injection for hospital use.


Mode of action

Cyclooxygenase (COX) has two well-studied isoforms, called COX-1 and COX-2. COX-1 mediates the synthesis of prostaglandinsresponsible for protection of the stomach lining, while COX-2 mediates the synthesis of prostaglandins responsible for pain and inflammation. By creating “selective” NSAIDs that inhibit COX-2, but not COX-1, the same pain relief as traditional NSAIDs is offered, but with greatly reduced risk of fatal or debilitating peptic ulcers. Rofecoxib is a selective COX-2 inhibitor, or “coxib”.

Others include Merck’s etoricoxib (Arcoxia), Pfizer’s celecoxib (Celebrex) and valdecoxib (Bextra). Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen.[4]


The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%.[5][6][7] Rofecoxib crossed the placenta and blood–brain barrier,[5][6][8]and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) of approximately 17 hours.[5][7][9] The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib[5][9] which are primarily excreted through urine.

Fabricated efficacy studies

On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as celecoxib) had been fabricated in order to augment the analgesic effects of the drugs. There is no evidence that Reuben colluded with Merck in falsifying his data. Reuben was also a former paid spokesperson for the drug company Pfizer (which owns the intellectual property rights for marketing celecoxib in the United States). The retracted studies were not submitted to either the FDA or the European Union’s regulatory agencies prior to the drug’s approval. Drug manufacturer Merckhad no comment on the disclosure.[10]

Adverse drug reactions

VIOXX sample blister pack.jpg

Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs.

Prostaglandin is a large family of lipids. Prostaglandin I2/PGI2/prostacyclin is just one member of it. Prostaglandins other than PGI2 (such as PGE2) also play important roles in vascular tone regulation. Prostacyclin/thromboxane are produced by both COX-1 and COX-2, and rofecoxib suppresses just COX-2 enzyme, so there is no reason to believe that prostacyclin levels are significantly reduced by the drug. And there is no reason to believe that only the balance between quantities of prostacyclin and thromboxane is the determinant factor for vascular tone.[11] Indeed Merck has stated that there was no effect on prostacyclin production in blood vessels in animal testing.[12] Other researchers have speculated that the cardiotoxicity may be associated with maleic anhydride metabolites formed when rofecoxib becomes ionized under physiological conditions. (Reddy & Corey, 2005)

Adverse cardiovascular events

VIGOR study and publishing controversy

The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., which compared the efficacy and adverse effect profiles of rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups, nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accidenttransient ischemic attack, or coronary artery bypass).

Merck’s scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks “is primarily due to” this protective effect (Targum, 2001). Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference (Michaels 2005), and some outside scientists warned Merck that this claim was implausible before VIGOR was published.[13] No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin.[14][15] Though Dr. Topol’s 2004 paper criticized Merck’s naproxen hypothesis, he himself co-authored a 2001 JAMA article stating “because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a prothrombotic effect from rofecoxib.” (Mukherjee, Nissen and Topol, 2001.)

The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, “Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen).”[16] This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).

Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, the journal editors learned that certain data reported to the FDA were not included in the NEJM article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data.[17] They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial.[18]

The editors charged that “more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article.” These additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the “aspirin not indicated” group) and the editors noted that the omission “resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups.” The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statitistically insignificant). The editors also noted a statistically significant (2-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication.[19]

The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection and thus were appropriately not included. (Utilizing the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the “omitted” table were printed in the text of the article. The authors stood by the original article.[20]

NEJM stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks).[19]

Some scientists have accused the NEJM editorial board of making unfounded accusations.[21][22] Others have applauded the editorial. Renowned research cardiologist Eric Topol,[23] a prominent Merck critic, accused Merck of “manipulation of data” and said “I think now the scientific misconduct trial is really fully backed up”.[24] Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying “this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies”.[25]

On May 15, 2006, the Wall Street Journal reported that a late night email, written by an outside public relations specialist and sent to Journal staffers hours before the Expression of Concern was released, predicted that “the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine‘s own role in aiding Vioxx sales.”[26]

“Internal emails show the New England Journal’s expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal’s handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article.” The Journal stated that NEJM‘s “ambiguous” language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; “the New England Journal says it didn’t attempt to have these mistakes corrected.”[26]

Alzheimer’s studies

In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer’s disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk due to rofecoxib.[27] Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib’s safety.

APPROVe study

In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for theprophylaxis of colorectal polypsCelecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (includingheart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations.[28]

In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

Other studies

Pre-approval Phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first eighteen months of rofecoxib usage (Merck, 2004). Others have pointed out that “study 090,” a pre-approval trial, showed a 3-fold increase in cardiovascular events compared to placebo, a 7-fold increase compared to nabumetone (another [NSAID]), and an 8-fold increase in heart attacks and strokes combined compared to both control groups.[29][30] Although this was a relatively small study and only the last result was statistically significant, critics have charged that this early finding should have prompted Merck to quickly conduct larger studies of rofecoxib’s cardiovascular safety. Merck notes that it had already begun VIGOR at the time Study 090 was completed. Although VIGOR was primarily designed to demonstrate new uses for rofecoxib, it also collected data on adverse cardiovascular outcomes.

Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using Kaiser Permanente data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005).

Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia.[31]

Other COX-2 inhibitors

Any increased risk of renal and arrhythmia pathologies associated with the class of COX-2 inhibitors, e.g. celecoxib (Celebrex), valdecoxib (Bextra), parecoxib (Dynastat),lumiracoxib, and etoricoxib is not evident,[31] although smaller studies[32][33] had demonstrated such effects earlier with the use of celecoxib, valdecoxib and parecoxib.

Nevertheless, it is likely that trials of newer drugs in the category will be extended in order to supply additional evidence of cardiovascular safety. Examples are some more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), which are currently (circa 2005) undergoing Phase III/IV clinical trials.

Besides, regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors:[34]

  • Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease
  • Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking
  • Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment

Other NSAIDs

Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sort of trials have never been carried out in older “trusted” NSAIDs such as ibuprofendiclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet aggregation properties.


Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.[35]

In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.[36]

On November 5, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Jüni omitted several studies that showed no increased cardiovascular risk. (Merck & Co., 2004).

In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib’s benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen—though the panel recommended that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market.[37]

In 2005, Merck retained Debevoise & Plimpton LLP to investigate Vioxx study results and communications conducted by Merck. Through the report, it was found that Merck’s senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the sales team’s overzealous behavior. The report that was filed gave a timeline of the events surrounding Vioxx and showed that Merck intended to operate honestly throughout the process. Any mistakes that were made regarding the mishandling of clinical trial results and withholding of information was the result of oversight, not malicious behavior. The Martin Report did conclude that the Merck’s marketing team exaggerated the safety of Vioxx and replaced truthful information with sales tactics.[citation needed] The report was published in February 2006, and Merck was satisfied with the findings of the report and promised to consider the recommendations contained in the Martin Report. Advisers to the US Food and Drug Administration (FDA) have voted, by a narrow margin, that it should not ban Vioxx — the painkiller withdrawn by drug-maker Merck.

They also said that Pfizer’s Celebrex and Bextra, two other members of the family of painkillers known as COX-2 inhibitors, should remain available, despite the fact that they too boost patients’ risk of heart attack and stroke. url = The recommendations of the arthritis and drug safety advisory panel offer some measure of relief to the pharmaceutical industry, which has faced a barrage of criticism for its promotion of the painkillers. But the advice of the panel, which met near Washington DC over 16–18 February, comes with several strings attached.

For example, most panel members said that manufacturers should be required to add a prominent warning about the drugs’ risks to their labels; to stop direct-to-consumer advertising of the drugs; and to include detailed, written risk information with each prescription. The panel also unanimously stated that all three painkillers “significantly increase the risk of cardiovascular events”.

The panel voted 17 to 15 against banning Vioxx (rofecoxib) entirely; the vote on Bextra (valdecoxib) was 17 to 13 with 2 abstentions; Celebrex (celecoxib) was endorsed 31 to 1. Shares of Merck, based in Whitehouse Station, New Jersey, and New York-based Pfizer closed up 13% and 7% respectively on 18 February, 2013, the day of the votes.

The FDA is expected to act on the recommendations within weeks. Although the agency usually follows the recommendations of its outside advisers, it is not bound to do so. A top official said that, in light of the closeness of some of the votes, the agency will examine the panel members’ comments in detail before deciding what to do.

An official from Merck said during the meeting that it would consider reintroducing Vioxx, which it withdrew in September 2004. On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on recommendation by the FDA. Pfizer’s other painkiller, Celebrex, is still on the market.


As of March 2006, there had been over 10,000 cases and 190 class actions filed against Merck[citation needed] over adverse cardiovascular events associated with rofecoxib and the adequacy of Merck’s warnings. The first wrongful death trial, Rogers v. Merck, was scheduled in Alabama in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use.[1]

On August 19, 2005, a jury in Texas voted 10-2 to hold Merck liable for the death of Robert Ernst, a 59-year-old man who allegedly died of a rofecoxib-induced heart attack. The plaintiffs’ lead attorney was Mark Lanier. Merck argued that the death was due to cardiac arrhythmia, which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award will almost certainly be capped at no more than US$26.1 million because of punitive damages limits under Texas law.[2] As of March 2006, the plaintiff had yet to ask the court to enter a judgment on the verdict; Merck has stated that it will appeal.

On November 3, 2005, Merck won the second case Humeston v. Merck, a personal injury case, in Atlantic City, New Jersey. The plaintiff experienced a mild myocardial infarction and claimed that rofecoxib was responsible, after having taken it for two months. Merck argued that there was no evidence that rofecoxib was the cause of Humeston’s injury and that there is no scientific evidence linking rofecoxib to cardiac events with short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug’s risk.[3]

The first federal trial on rofecoxib, Plunkett v. Merck, began on November 29, 2005 in Houston. The trial ended in a hung jury and a mistrial was declared on December 12, 2005. According to the Wall Street Journal, the jury hung by an eight to one majority, favoring the defense. Upon retrial in February 2006 in New Orleans, where the Vioxx multidistrict litigation (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study.

On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastrointestinal bleeding that he experienced after taking the drug. The judge said that Boyd failed to prove the drug caused his stomach pain and internal bleeding.

In January 2006, Garza v. Merck began trial in Rio Grande City, Texas. The plaintiff, a 71-year-old smoker with heart disease, had a fatal heart attack three weeks after finishing a one-week sample of rofecoxib. On April 21, 2006 the jury awarded the plaintiff $7 million compensatory and $25 million punitive. The Texas state court of appeals in San Antonio later rules Garza’s fatal heart attack probably resulted from pre-existing health conditions unrelated to his taking of Vioxx, thus reversing the $32 million jury award.[4]

On April 5, 2006, the jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded Mr McDarby $4.5 million in compensatory damages based on Merck’s failure to properly warn of Vioxx safety risks. After a hearing on April 11, 2006, the jury also awarded Mr McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial, but was liable for fraud in the sale of the drug to Cona.

Merck has reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens. Patients who claim to have suffered as a result of taking Vioxx in countries outside the US are campaigning for this to be extended.

In March 2010, an Australian class-action lawsuit against Merck ruled that Vioxx doubled the risk of heart attacks, and that Merck had breached the Trade Practices Act by selling a drug which was unfit for sale.[38]

In November 2011, Merck announced a civil settlement with the US Attorney’s Office for the District of Massachusetts, and individually with 43 US states and the District of Columbia, to resolve civil claims relating to Vioxx.[5] Under the terms of the settlement, Merck agreed to pay two-thirds of a previously recorded $950 million reserve charge in exchange for release from civil liability. Litigation with seven additional states remains outstanding. Under separate criminal proceedings, Merck plead guilty to a federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million.[6]

Other effects

Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.[39]


Rofecoxib synthesis.[40]



The oxidation of 4- (methylsulfanyl) acetophenone (X) with monoperoxyphthalic acid (MMPP) in dichloro-methane / methanol gives the corresponding sulfone (XI), which is brominated with Br2 / AlCl3 in chloroform, yielding the expected phenacyl bromide ( XII). Finally, this compound is cyclocondensed with phenylacetic acid (I) by means of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and triethylamine in acetonitrile. 5) Reaction of [4- (methylsulfonyl ) phenyl] phenylacetyl-ene (XIII) with CO catalyzed by Rh4 (CO) 12 in THF at 100 C in a stainless steel autoclave at 100 Atm pressure, followed by a chromatographic separation in a silicagel column to eliminate the undesired regioisomer.



The synthesis of rofecoxib can be performed by several different ways: 1) The condensation of phenylacetic acid (I) with ethyl bromoacetate (II) by means of triethylamine in THF yields 2- (phenylacetoxy) acetic acid ethyl ester (III), which is cyclized to the hydroxyfuranone (IV) by means of potassium tert-butoxide in tert-butanol. The reaction of (IV) with triflic anhydride and diisopropylethylamine in dichloro-methane affords the corresponding triflate (V), which by reaction with LiBr in hot acetone yields the bromofuranone (VI) The condensation of (VI) with 4- (methylsulfanyl) phenylboronic acid (VII) by means of Na2CO3 and Pd (Ph3P) 4 in hot toluene gives 4- [4- (methylsulfanyl) -phenyl]. – 3-phenylfuran-2 (5H) -one (VIII), which is finally oxidized with 2KHSO5.KHSO4.K2SO4 (oxone). 2) The intermediate (VIII) can also be obtained by condensation of triflate (V) with boronic acid ( VII) by means of Na2CO3 and Pd (Ph3P) 4 in hot toluene. 3) The intermediate (VIII) can also be synthesized by the reaction of triflate (V) with tetramethylammonium chloride, giving the chlorofuranone (IX), which is then condensed with boronic acid (VII) as before.


  2.  “Up to 140,000 heart attacks linked to Vioxx.”New Scientist. 2005-01-25. p. 1.
  3.  “Merck Sees Slightly Higher 2007 Earnings”New York Times. Reuters. 2006-12-07. p. A1.
  4.  Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M. B.; Hawkey, C. J.; Hochberg, M. C.; Kvien, T. K.; Schnitzer, T. J.; Vigor Study, G. (2000). “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis”. New England Journal of Medicine 343 (21): 1520–1528, 2 1528 following 1528. doi:10.1056/NEJM200011233432103PMID 11087881edit
  5. Merck & Co. VIOXX (rofecoxib tablets and oral suspension). Accessed at: 01 Feb 2010
  6.  Gold Standard Inc. Rofecoxib Vioxx Accessed at: 01 Feb 2010
  7. Jump up to:a b Davies, N. M.; Teng, X. W.; Skjodt, N. M. (2003). “Pharmacokinetics of rofecoxib: a specific cyclo-oxygenase-2 inhibitor”. Clinical pharmacokinetics 42 (6): 545–556.PMID 12793839edit
  8.  Padi, S.; Kulkarni, S. (2004). “Differential effects of naproxen and rofecoxib on the development of hypersensitivity following nerve injury in rats”. Pharmacology, Biochemistry, and Behavior 79 (2): 349–358. doi:10.1016/j.pbb.2004.08.005PMID 15501312edit
  9. Scott, L. J.; Lamb, H. M. (1999). “Rofecoxib”. Drugs 58 (3): 499–505; discussion 506–7. doi:10.2165/00003495-199958030-00016PMID 10493277edit
  10.  Winstein, Keith J. (March 11, 2009). “Top Pain Scientist Fabricated Data in Studies, Hospital Says”The Wall Street Journal.
  11.  Vane, J.; Bakhle, Y.; Botting, R. (1998). “Cyclooxygenases 1 and 2”. Annual review of pharmacology and toxicology 38: 97–120. doi:10.1146/annurev.pharmtox.38.1.97.PMID 9597150edit
  13. Jump up^
  14.  Karha, J.; Topol, E. J. (2004). “The sad story of Vioxx, and what we should learn from it”. Cleveland Clinic journal of medicine 71 (12): 933–934, 936, 934–9.doi:10.3949/ccjm.71.12.933PMID 15641522edit
  15.  Solomon, D. H.; Glynn, R. J.; Levin, R.; Avorn, J. (2002). “Nonsteroidal anti-inflammatory drug use and acute myocardial infarction”. Archives of Internal Medicine 162 (10): 1099–1104.doi:10.1001/archinte.162.10.1099PMID 12020178edit
  17.  Curfman, G.; Morrissey, S.; Drazen, J. (2005). “Expression of concern: Bombardier et al., “Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis,” N Engl J Med 2000;343:1520-8″. The New England Journal of Medicine 353 (26): 2813–2814. doi:10.1056/NEJMe058314PMID 16339408edit
  18. Missing or empty |title= (help)[dead link]
  19.  Curfman, G.; Morrissey, S.; Drazen, J. (2006). “Expression of concern reaffirmed”. The New England Journal of Medicine 354 (11): 1193. doi:10.1056/NEJMe068054.PMID 16495386edit
  20. Jump up^ Bombardier, C.; Laine, L.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M.; Hawkey, C.; Hochberg, M.; Kvien, T.; Schnitzer, T. J.; Weaver, A. (2006). “Response to expression of concern regarding VIGOR study”. The New England Journal of Medicine 354 (11): 1196–1199. doi:10.1056/NEJMc066096PMID 16495387edit
  24. Jump up^
  26. David Armstrong (2006-05-15). “How the New England Journal Missed Warning Signs on Vioxx”Wall Street Journal. p. A1.
  27.  Konstam, M. A.; Weir, M. R.; Reicin, A.; Shapiro, D.; Sperling, R. S.; Barr, E.; Gertz, B. J. (2001). “Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib”. Circulation104 (19): 2280–2288. doi:10.1161/hc4401.100078PMID 11696466edit
  28. Bresalier, R.; Sandler, R.; Quan, H.; Bolognese, J.; Oxenius, B.; Horgan, K.; Lines, C.; Riddell, R.; Morton, D.; Lanas, A.; Konstam, M. A.; Baron, J. A.; Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators (2005). “Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial”. The New England Journal of Medicine 352(11): 1092–1102. doi:10.1056/NEJMoa050493PMID 15713943edit
  30. Jump up^ Wolfe, M. M. (2004). “Rofecoxib, Merck, and the FDA”. The New England Journal of Medicine 351 (27): 2875–2878; author 2878 2875–2878. doi:10.1056/NEJM200412303512719.PMID 15625749edit
  31.  Zhang, J.; Ding, E.; Song, Y. (2006). “Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials”. Journal of the American Medical Association 296 (13): 1619–1632. doi:10.1001/jama.296.13.jrv60015PMID 16968832edit
  32. Solomon, S.; McMurray, J.; Pfeffer, M.; Wittes, J.; Fowler, R.; Finn, P.; Anderson, W.; Zauber, A.; Hawk, E.; Bertagnolli, M.; Adenoma Prevention with Celecoxib (APC) Study Investigators (2005). “Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention”. The New England Journal of Medicine 352 (11): 1071–1080.doi:10.1056/NEJMoa050405PMID 15713944edit
  33.  Nussmeier, N.; Whelton, A.; Brown, M.; Langford, R.; Hoeft, A.; Parlow, J.; Boyce, S.; Verburg, K. (2005). “Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery”. The New England Journal of Medicine 352 (11): 1081–1091. doi:10.1056/NEJMoa050330PMID 15713945edit
  34.  “European Medicines Agency concludes action on COX-2 inhibitors” (pdf). European Medicines Agency. Retrieved 2008-04-16.
  35.  “Merck Announces Voluntary Worldwide Withdrawal of VIOXX” (pdf). Retrieved 2008-04-16.
  36.  “Congress Questions Vioxx, FDA”PBS NewsHour. 2004-11-18. Retrieved 2013-06-03.
  37.  “SUMMARY: Report of the Expert Advisory Panel on the Safety of Cox-2 Selective Non-steroidal Anti-Inflammatory Drugs (NSAIDs)”Health Canada. 2005-07-06. Retrieved 2011-06-04.
  38.  Drug unfit for sale, says judge in compo case The Age, March 6, 2010


  • FDA (2005). “Summary minutes for the February 16, 17 and 18, 2005, Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee.” Published on the internet, March 2005. Link
  • Fitzgerald GA, Coxibs and Cardiovascular Disease, N Engl J Med 2004;351(17): 1709–1711. PMID 15470192.
  • Grassley CE (15 Oct 2004). Grassley questions Merck about communication with the FDA on Vioxx. Press Release.
  • Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M (2004). Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet (published online; see also Merck response below)
  • Karha J and Topol EJ. The sad story of Vioxx, and what we should learn from it Cleve Clin J Med 2004; 71(12):933-939. PMID 15641522
  • Michaels, D. (June 2005) DOUBT Is Their ProductScientific American, 292 (6).
  • Merck & Co., (5 Nov 2004). Response to Article by Juni et al. Published in The Lancet on Nov. 5. Press Release.
  • Merck & Co (30 Sep 2004) Merck Announces Voluntary Worldwide Withdrawal of VIOXX. Press release [7].
  • D. M. Mukherjee, S. E. Nissen, and E. J. Topol, “Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors,” Journal of the American Medical Association 186 (2001): 954–959.
  • Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352(11):1081-91. PMID 15713945
  • Okie, S (2005) “Raising the safety bar–the FDA’s coxib meeting.” N Engl J Med. 2005 Mar 31;352(13):1283-5. PMID 15800221.
  • Leleti Rajender Reddy, Corey EJ. Facile air oxidation of the conjugate base of rofecoxib (Vioxx), a possible contributor to chronic human toxicity Tetrahedron Lett 2005, 46: 927. doi:10.1016/j.tetlet.2004.12.055
  • Swan SK et al., Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet. Annals of Int Med 2000; 133:1–9
  • Targum, SL. (1 Feb. 2001) Review of cardiovascular safety database. FDA memorandum. [8]
  • Wolfe, MM et al., Gastrointestinal Toxicity of Nonsteroidal Anti-anflamattory Drugs, New England Journal of Medicine. 1999; 340; 1888-98.

External links


Literature References:

Selective cyclooxygenase-2 (COX-2) inhibitor. Prepn: Y. Ducharme et al., WO 9500501; eidem, US5474995 (both 1995 to Merck Frosst).

HPLC determn in plasma: C. M. Chavez-Eng et al., J. Chromatogr. B 748, 31 (2000).

Enzyme inhibition and clinical evaluation in dental pain: E. W. Ehrich et al., Clin. Pharmacol. Ther. 65, 336 (1999).

Evaluation of risk of gastrointestinal effects in patients with osteoarthritis: M. J. Langman et al., J. Am. Med. Assoc. 282, 1929 (1999); with rheumatoid arthritis: C. Bombardier et al., N. Engl. J. Med. 343, 1520 (2000).

Review of pharmacology and clinical experience: A. J. Matheson, D. P. Figgitt, Drugs 61, 833-865 (2001).

Keywords: Cyclooxygenase-2 Selective Inhibitor, Anti-inflammatory (Nonsteroidal), Analgesic (Non-Narcotic), rofecoxib, MK-0966, Vioxx










KYORIN Kyorin Seiyaku Kk……….INNOVATOR

Properties: Crystals from hexane, mp 53.5-54°. Slightly sol in water, freely sol in organic solvents. LD50 i.v. in mice: 260 mg/kg (Irikura, 1973).
Melting point: mp 53.5-54°
Toxicity data: LD50 i.v. in mice: 260 mg/kg (Irikura, 1973)
Therap-Cat: Antiallergic; antiasthmatic; vasodilator (cerebral).

Ibudilast is an anti-inflammatory and neuroprotective oral agent which shows an excellent safety profile at 60 mg/day and provides significantly prolonged time-to-first relapse and attenuated brain volume shrinkage in patients with relapsing-remitting (RR) and/or secondary progressive (SP) multiple sclerosis (MS). Ibudilast is currently in development in the U.S. (codes: AV-411 or MN-166), but is approved for use as an antiinflammatory in Japan.

CAS: 50847-11-5, Ibudilastum, Ketas, KC-404, MN-166, Ke Tas
Molecular Formula:C14H18N2O
Molecular Weight:230.30552 g/mol
Ibudilast is a leukotriene antagonist and phosphodiesterase inhibitor which has been commercialized in Japan and other parts of Asia for over 15 years as capsules for the treatment of bronchial asthma and cerebrovascular disturbances. In 2000, the product was launched for the topical treatment of allergic conjunctivitis. At present, the drug is undergoing phase II trials at MediciNova for the oral treatment of multiple sclerosis (MS), for the treatment of medication overuse headache (MOH), for the treatment of diabetic neuropathic pain, for the treatment of methamphetamine addiction and for the treatment of opioid withdrawal.
Early clinical trials are ongoing for the treatment of amyotrophic lateral sclerosis as an adjunt to riluzole.MediciNova and the University of Colorado had been evaluating the product in preclinical studies for the treatment of post-traumatic brain injury; however, no recent development has been reported for this research.Ibudilast exhibits antiplatelet properties mainly by inhibiting phosphodiesterase V (PDE V), which in turn potentiates antiplatelet function of endothelium-derived nitric oxide (NO). The compound has also been shown to suppress hippocampal apoptosis induced by amyloid beta hypoxia.




Ibudilast (development codes: AV-411 or MN-166) is an antiinflammatory drug used mainly in Japan, which acts as aphosphodiesterase inhibitor, inhibiting the PDE-4 subtype to the greatest extent,[1] but also showing significant inhibition of other PDE subtypes.[2][3]

Ibudilast has bronchodilator, vasodilator [4] and neuroprotective effects,[5][6] and is mainly used in the treatment of asthma andstroke.[7] It inhibits platelet aggregation,[8] and may also be useful in the treatment of multiple sclerosis.[9]

Ibudilast crosses the blood–brain barrier and suppresses glial cell activation. This activity has been shown to make ibudilast useful in the treatment of neuropathic pain and it not only enhances analgesia produced by opioid drugs, but also reduces the development oftolerance.[10]

It may have some use reducing methamphetamine[11] and alcohol[12] addiction.

It may have some use reducing methamphetamine addiction.[11]

Avigen has identified the potential of ibudilast (AV-411) for the treatment of neuropathic pain and other neurological indications, including opiate withdrawal. As an inhibitor of glial cells, ibudilast can deactivate these cells which produce various chemicals, including proinflammatory cytokines, in response to nerve damage or viral infection to amplify and maintain pain. Preclinical evaluation to date indicates that it reverses the painful sensory abnormality allodynia in chemotherapy- and trauma-induced neuropathic pain models.

Originator Kyorin and Banyu Pharmaceutical (now MSD KK following the merger of Banyu and Schering-Plough KK in 2010) have been developing ibudilast under a collaborative agreement. MediciNova obtained exclusive, worldwide rights outside of Japan, China, Taiwan and South Korea from Kyorin in October 2004 to develop and commercialize the compound for MS. In 2012, a codevelopment agreement was signed between MediciNova and the University of Colorado for the treatment of post-traumatic brain injury.

Sixteenth revised Japanese Pharmacopoeia chemicals, etc. IBUDILAST  Ibudilast C14H18N2O: 230.31 [ 50847-11-5 ] that this product was dried when to quantify, including ibudilast (C14H18N2O) 98.5 ~ 101.0%.

EXAMPLE 1 Synthesis of 2-isopropyl-3-is0butyrylpyrazolo[1,5-a] pyridine (KC404) A mixture of 1-amino-Z-methylpyridinium iodide g.), isobutyric anhydride (500 g.) and K CO (81 g.) was refluxed for 8 hr. After cooling, the precipitated crystals were filtered off and water was added to the filtrate, The solution was made basic to pH 11 with K CO’ and extracted with ethyl acetate (1000 ml.). The extract’was washed with water (400 ml.), dried over Na SO and concentrated under reduced pressure. The residue was distilled to give 58 g. of colorless crystalline product, hp, 110- 175 (7.5 mm. Hg). Recrystallization from hexane gave colorless prisms, melting point 53.554.

Analysis- Calcd.: C, 73.01; H, 7.88; N, 12.17 Found: C, 72.86; H, 7.94; N, 12.09



FIG. 6 is a synthetic reaction scheme illustrating one approach for preparing (S)-AV1013; the approach employs chiral chromatography of an N-protected form of the racemate as described in detail in Example 1.

FIG. 7 demonstrates additional reaction schemes for synthesizing (S)-AV1013.




Example 1Synthesis of (S)-2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one hydrochloride

(S)-2-Amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one hydrochloride (also referred to herein as S-AV1013.HCl) was prepared on a preparative scale using two different routes to obtain the intermediate isopropylpyrazolo[1,5-a]pyridine (IPPP). In the first approach (method 1), ibudilast was employed as the starting material to obtain IPPP; an alternate synthetic approach (method 2) employed ibudilast acid as the starting material.

Step 1Method 1Preparation of Isopropylpyrazolo[1,5-a]pyridine (IPPP) from ibudilast

Figure US08119657-20120221-C00002

A 5 L 3-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple, heating mantle and a Y-adapter with a nitrogen inlet. The flask was charged with water (350 mL, USP), concentrated sulfuric acid (350 mL) and ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) (140 g, 0.608 mol). The flask was purged with nitrogen, and the mixture was stirred while it was heated to 135° C. An aliquot was removed for HPLC analysis, which showed that all starting material was consumed after 5 hours at 135° C., so the mixture was allowed to cool to room temperature overnight. The mixture was cooled in an ice bath, and water (1400 mL, USP) was added over 10 min, with the temperature maintained below 25° C. With continuous cooling in an ice bath, the mixture was neutralized by adding sodium hydroxide (50% w/w aq., 1150 mL) dropwise, with the temperature maintained below 25° C. Ethyl acetate (250 mL) was added, and the layers were separated. The aqueous layer was washed with ethyl acetate (2×300 mL). The combined ethyl acetate extracts were washed sequentially with 250 mL portions of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate for 30 minutes. Activated carbon (20 g) and silica (60 g) were added and stirred before filtering over a pad of Celite. The filtrate was concentrated under reduced pressure to obtain 96.5 g of IPPP (2-isopropyl-pyrazolo[1,5-a]pyridine, 99% crude yield, 99.6 area % pure by HPLC) as an amber oil.

1H-NMR (CDCl3) δ 1.4 (d, 6H), 3.2 (m, 1H), 6.3 (s, 1H), 6.6 (t, 1H), 7.0 (m, 1H), 7.4 (d, 1H), 8.4 (d, 1H). HPLC: RT=9.1 min (99.6 area %).



Ibudilast (3-isobutyryl-2-isopropylpyrazolo[l,5-α]pyridine) is a small molecule drug that has been used for many years in Japan and Korea for the treatment of bronchial asthma as well as for treatment of cerebrovascular disorders such as post-stroke dizziness. It is sold in these countries under the tradename, Ketas®. Marketed indications for ibudilast in Japan include its use as a vasodilator, for treating allergy, eye tissue regeneration, ocular disease, and treatment of allergic ophthalmic disease (Thompson Current Drug Reports). Its use in the treatment of both chronic brain infarction ( and multiple sclerosis (News.Medical.Net; Pharmaceutical News, 2 Aug 2005) is currently being explored in separate, ongoing clinical trials.

The mechanisms of action of ibudilast have been widely explored. Its role as a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) has been described

(Fujimoto, T., et al., J. of Neuroimmunology, 95 (1999) 35-92). Additionally, ibudilast has been reported to act as an LTD4 antagonist, an anti-inflammatory, a PAF antagonist, and a vasodilatator agent (Thompson Current Drug Reports). Ibudilast is also thought to exert a neuroprotective role in the central nervous system of mammals, presumably via suppression of the activation of glial cells (Mizuno et al. (2004) Neuropharmacology 46: 404-411). New uses for ibudilast continue to be explored.



Ibudilast is a small molecule drug (molecular weight of 230.3) having the structure shown below.

Figure imgf000011_0001

Ibudilast is also found under ChemBank ID 3227, CAS # 50847-1 1-5, and Beilstein Handbook Reference No. 5-24-03-00396. Its molecular formula corresponds to [Ci4HIgN2O]. Ibudilast is also known by various chemical names which include 2- methyl-l-(2-(l-methylethyI)pyrazolo(l,5-a)pyridin-3-yl)l-propanone; 3-isobutyryl-2- isopropylpyrazolo(l,5-a)pyridine]; and l-(2-isopropyl-pyrazolo[l,5-a]pyridin-3-yl)-2- methyl-propan-1-one. Other synonyms for ibudilast include Ibudilastum (Latin), BRN 0656579, KC-404, and the brand name Ketas®. Ibudilast, as referred to herein, is meant to include any and all pharmaceutically acceptable salt forms thereof, prodrug forms (e.g., the corresponding ketal), and the like, as appropriate for use in its intended formulation for administration.

Ibudilast is a non-selective nucleotide phosphodiesterase (PDE) inhibitor (most active against PDE-3 and PDE-4), and has also been reported to have LTD4 and PAF antagonistic activities. Its profile appears effectively anti-inflammatory and unique in comparison to other PDE inhibitors and anti-inflammatory agents. PDEs catalyze the hydrolysis of the phosphoester bond on the 3 -carbon to yield the corresponding 5′- nucleotide monophosphate. Thus, they regulate the cellular concentrations of cyclic nucleotides. Since extracellular receptors for many hormones and neurotransmitters utilize cyclic nucleotides as second messengers, the PDEs also regulate cellular responses to these extracellular signals. There are at least eight classes of PDEs: Ca2+/calmodul in-dependent PDEs (PDEl); cGMP-stimulated PDEs (PDE2); cGMP- inhibited PDEs (PDE3); cAMP-specific PDEs (PDE4); cGMP-binding PDEs (PDE5); photoreceptor PDEs (PDE6); high affinity, cAMP-specific PDEs (PDE7); and high affinity cGMP-specific PDEs (PDE9).


DE 2315801; FR 2182914; JP 7714799, WO 0196278

By condensation of 1-amino-2-methylpyridinium iodide (I) with isobutyric anhydride (II) by means of K2CO3 at reflux temperature.


 US 20140037547


CN 102617579

2-methyl -l- [2- (l- methylethyl) – pyrazolo [l, 5_a] pyrimidine _3_ yl] _1_ acetone (ibudilast, generic drug name: IBUDILAST ) is an anti-allergic asthma drugs, anti-leukotrienes can twist and platelet-activating factor, promote the secretion of mucus in the respiratory tract, respiratory cilia function, enhance the role of prostacyclin, increase cerebral blood flow, improve brain metabolism. For the treatment of bronchial asthma, sequelae of cerebral embolism, cerebral arteriosclerosis.

 ibudilast preparation methods are mainly the following two:

 Method a: (The Jourrtal of Organic Chemistry, 1968, 33, 3766 ~3770) Synthesis Road

Lines are as follows:


Figure CN102617579AD00041

 The route to 2-picoline as starting material to give amino-2-methyl-pyridine iodide I-, after pyrimidine, the role of isobutyryl chloride to give the title compound. The final product obtained by this route need be purified by column chromatography, thereby increasing the difficulty of the operation, in addition to column chromatography, eluent used larger benzene toxicity, is not suitable for industrial production.

 Method II: (Journal of the American Chemical Society, 2005,127, 751-760) co

A route is as follows:


Figure CN102617579AD00042

The route to 2-picoline as starting material to obtain the sulfamic acid, potassium iodide I- amino-2-picoline under the action of potassium carbonate, then with isobutyric anhydride to give the title compound effect. This route of the first-stage reaction process locked, the yield is low, is not suitable for industrial production.

 so there ibudilast conventional method for preparing the operational difficulties or low yield, making it impossible to achieve industrial production problems.

DETAILED DESCRIPTION IX: with a specific embodiment of the present embodiment is one of one to eight different points: in the second step of the recrystallization specific operation is as follows: First, the collected fractions was cooled to 10 ° c~25 ° C, to give a pale yellow solid, and then n-hexane was added to the pale yellow solid, and the temperature was raised to 50 ° C~68 ° C, at a temperature of 50 ° C~68 ° C incubation 5min~IOmin, then cooled to 10 ° C~ 25 ° C, and at a temperature of 10 ° C~25 ° C incubated O. 5h~Ih, and finally filtered to obtain ibudilast; the volume of the pale yellow solid quality and hexane ratio of Ig: (ImL~2mL), to obtain ibudilast.


Bioorganic & medicinal chemistry letters (2011), 21(11), 3307-12.

Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure–activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7′ in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3′-centre to C-4′ strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.

Image for unlabelled figure




…………..MediciNova’s ibudilast gets FDA rare paediatric disease status to treat Krabbe disease
MediciNova has received rare paediatric disease status from the US Food and Drug Administration (FDA) for its MN-166 (ibudilast) to treat Type 1 Early Infantile Krabbe disease.


  1.  Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K. Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sciences. 2006 May 1;78(23):2663-8.
  2.  Suzumura A, Ito A, Yoshikawa M, Sawada M. Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Research. 1999 Aug 7;837(1-2):203-12.
  3.  Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. European Journal of Pharmacology. 2006 May 24;538(1-3):39-42.
  4.  Kishi Y, Ohta S, Kasuya N, Sakita S, Ashikaga T, Isobe M. Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall. Cardiovascular Drug Reviews. 2001 Fall;19(3):215-25.
  5.  Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Suzumura A. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology. 2004 Mar;46(3):404-11.
  6.  Yoshioka M, Suda N, Mori K, Ueno K, Itoh Y, Togashi H, Matsumoto M. Effects of ibudilast on hippocampal long-term potentiation and passive avoidance responses in rats with transient cerebral ischemia. Pharmacological Research. 2002 Apr;45(4):305-11.
  7.  Wakita H, Tomimoto H, Akiguchi I, Lin JX, Ihara M, Ohtani R, Shibata M. Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. Brain Research. 2003 Nov 28;992(1):53-9.
  8.  Rile G, Yatomi Y, Qi R, Satoh K, Ozaki Y. Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells. Thrombosis Research. 2001 May 1;102(3):239-46.
  9.  Feng J, Misu T, Fujihara K, Sakoda S, Nakatsuji Y, Fukaura H, Kikuchi S, Tashiro K, Suzumura A, Ishii N, Sugamura K, Nakashima I, Itoyama Y. Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. Multiple Sclerosis. 2004 Oct;10(5):494-8.
  10. Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opinion on Investigational Drugs. 2007 Jul;16(7):935-50.

SEE……Synthesis technology of ibudilast
Shandong Huagong (2014), 43, (8), 29-30. Publisher: (Shandong Huagong Bianjibu, ) CODEN:SHHUA4 ISSN:1008-021X.


Literature References:

Leukotriene D4 antagonist. Prepn: T. Irikura et al., DE 2315801; eidem, US 3850941 (1973, 1974 both to Kyorin).

Pharmacology and antiallergic activity: K. Nishino et al., Jpn. J. Pharmacol. 33, 267 (1983); H. Nagai et al., ibid. 1215.

In vitro cerebral vasodilating activity: M. Ohashi et al., Arch. Int. Pharmacodyn. 280, 216 (1986);

in vivo activity: W. M. Armstead et al., J. Pharmacol. Exp. Ther. 244, 138 (1988).

Bronchodilating activity in animals: S. Mue et al., Arch. Int. Pharmacodyn. 283,153 (1986).

Antiplatelet activity in animals: M. Ohashi et al., ibid. 321; M. Ohashi et al., Gen. Pharmacol. 17, 385 (1986).

Patent Submitted Granted
Method for treating neuropathic pain and associated syndromes [US7534806] 2006-07-20 2009-05-19
Synergistic combination [US2006205806] 2006-09-14
Pharmaceutical composition of a pde4 or pde 3/4 inhibitor and histamine receptor antagonist [US2005112069] 2005-05-26
Methods and reagents for the treatment of immunoinflammatory disorders [US2005119160] 2005-06-02
Methods of inducing ovulation using a non-polypeptide camp level modulator [US7507707] 2005-07-07 2009-03-24
Methods and reagents for the treatment of immunoinflammatory disorders [US2005192261] 2005-09-01
Synergistic combination [US7056936] 2004-02-19 2006-06-06
Methods for the treatment of respiratory diseases and conditions with a selective iNOS inhibitor and a PDE inhibitor and compositions therefor [US2004087653] 2004-05-06
Remedies for multiple sclerosis [US6395747] 2002-05-28
Combination [US2005014762] 2005-01-20
 Patent Filing date Publication date Applicant Title
US4097483 Aug 31, 1976 Jun 27, 1978 Kyorin Pharmaceutical Co., Ltd. Pyrazolo 1,5-a!pyridines
US7585875 * Jun 6, 2007 Sep 8, 2009 Avigen, Inc. Phosphodiesterase inhibitors; neuropathic pain, inflammation, opioid dependence or withdrawal; 2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one for example
US20070015924 Jun 15, 2006 Jan 18, 2007 Cardiome Pharma Corp. stereoselective preparation of aminocyclohexyl ether compounds such as trans-(1R,2R)-aminocyclohexyl ether compounds and/or trans-(1S,2S)-aminocyclohexyl ether compounds; useful in treating arrhythmias
US20080070912 Jun 6, 2007 Mar 20, 2008 Avigen, Inc. Phosphodiesterase inhibitors; neuropathic pain, inflammation, opioid dependence or withdrawal; 2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one for example
US20090062330 Jul 8, 2008 Mar 5, 2009 Medicinova, Inc. Treatment of progressive neurodegenerative disease with ibudilast
US20090318437 * Jun 10, 2009 Dec 24, 2009 Gaeta Federico C A SUBSTITUTED PYRAZOLO[1,5-a] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE
WO2007142924A1 May 29, 2007 Dec 13, 2007 Avigen Inc Ibudilast for inhibiting macrophage migration inhibitory factor (mif) activity
US8119657 Jun 22, 2010 Feb 21, 2012 Medicinova, Inc. Enantiomeric compositions of 2-amino-1-(2-isopropylpyrazolo[1,5-α]pyridin-3-yl)propan-1-one and related methods
Patent Filing date Publication date Applicant Title
WO2003104178A1 * Jun 6, 2003 Dec 18, 2003 Cortical Pty Ltd Napththalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (mif)
WO2003104203A1 * Jun 6, 2003 Dec 18, 2003 Cortical Pty Ltd Therapeutic molecules and methods-1
WO2004058713A1 * Dec 18, 2003 Jul 15, 2004 Jason Chyba Differential tumor cytotoxocity compounds and compositions
WO2005058304A1 * Dec 17, 2004 Jun 30, 2005 Cortical Pty Ltd Implantable device containing inhibitor of macrophage migration inhibitory factor
WO2006045505A1 * Oct 19, 2005 May 4, 2006 Novartis Ag Mif-inhibitors
WO2006108671A1 * Apr 13, 2006 Oct 19, 2006 Novartis Ag 3,4-dihydro-benzo[e][1,3]oxazin-2-ones
Systematic (IUPAC) name
Clinical data
AHFS/ International Drug Names
CAS Number 50847-11-5 Yes
ATC code R03DC04
PubChem CID: 3671
DrugBank DB05266 
ChemSpider 3543 
KEGG D01385 Yes
Chemical data
Formula C14H18N2O
Molecular mass 230.31 g/mol

Keywords: Antiallergic; Antiasthmatic (Nonbronchodilator); Leukotriene Antagonist; Vasodilator (Cerebral).




Piecing together the puzzle: understanding a mild, metal free reduction method for large scale synthesis of hydrazines


Piecing together the puzzle: understanding a mild, metal free reduction method for large scale synthesis of hydrazines

D.L. Browne,* I.R. Baxendale, S.V. Ley, Tetrahedron2011, 67, 10296-10303.

Full-size image (13 K)

A key intermediate for the synthesis of hydrazines via a mild, metal free reduction of diazonium salts has been isolated and characterized by X-ray analysis. The presence of this intermediate is general, as demonstrated by the preparation of a number of analogues. A discussion of the mechanism and potential benefits of such a process are also described.

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Multi-step synthesis using modular flow reactors: the preparation of yne-ones and their use in heterocycle synthesis

I.R. Baxendale, S.C. Schou, J. Sedelmeier, S.V. Ley, Chem. Eur. J. 2010, 16, 89-94.



Multi-step in flow: The palladium-catalysed acylation of terminal alkynes for the synthesis of yne[BOND]ones as well as their further transformation to various heterocycles in a continuous-flow mode is presented. Furthermore, an extension of the simple flow configuration that allows for easy batch splitting and the generation of a heterocyclic library is described (see scheme).



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