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Lumiracoxib…Selective cyclooxygenase-2-(COX-2) inhibitor. Anti-inflammatory.

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Lumiracoxib

2-[(2-Chloro-6-fluorophenyl)amino]-5-methylbenzeneacetic Acid;

2-[2-(2-Chloro-6-fluorophenylamino)-5-methylphenyl]acetic Acid;

CGS 35189; COX 189; Prexige;

Applications:   Selective cyclooxygenase-2-(COX-2) inhibitor. Anti-inflammatory.

Lumiracoxib
Systematic (IUPAC) name
{2-[(2-chloro-6-fluorophenyl)amino]-5-methylphenyl}
acetic acid
Clinical data
Trade names Prexige
AHFS/Drugs.com International Drug Names
Pregnancy cat. C (AU)
Legal status ℞-only
Withdrawn (Australia, New Zealand, Canada, UK, Germany,Austria, Belgium, Cyprus, Brazil)
Routes Oral
Pharmacokinetic data
Bioavailability 74-90%[1]
Protein binding >98%[1]
Metabolism Predominantly in the liver viaoxidation and hydroxylation(CYP2C9)[1]
Half-life 5-8 hours[1]
Excretion Urine (54%) and faeces (43%)[1]
Identifiers
CAS number  220991-20-8
ATC code M01AH06
PubChem CID 151166
DrugBank DB01283
ChemSpider 133236 Yes
UNII
PDB ligand ID LUR (PDBe, RCSB PDB)
Chemical data
Formula C15H13ClFNO2 
Mol. mass 293.72 g/mol

Lumiracoxib (rINN) is a carboxylic acid COX-2 selective inhibitor non-steroidal anti-inflammatory drug, manufactured by Novartis and still sold in few countries, including Mexico, Ecuador and the Dominican Republic, under the trade name Prexige (sometimes misquoted as “Prestige” by the media).[1]

Lumiracoxib has several distinctive features. Its structure is different from that of other COX-2 inhibitors, such as celecoxib: lumiracoxib is an analogue of diclofenac (one chlorine substituted by fluorine, the phenylacetic acid has another methyl group in meta position), making it a member of the arylalkanoic acid class of NSAIDs; it binds to a different site on the COX-2 enzyme than do other COX-2 inhibitors; it is the only acidic coxib and has the highest COX-2 selectivity of any NSAID.[2]

Since its original approval, lumiracoxib has been withdrawn from the market in several countries, mostly due to its potential for causing liver failure (sometimes requiring liver transplantation). It has never been approved for use in the United States.[1]

 

History

The TARGET study (Therapeutic Arthritis Research and Gastrointestinal Event Trial) was conducted with more than 18,000 patients to test its gastrointestinal and cardiovascular safety against naproxen and ibuprofen and also study its efficacy against these two NSAIDs.

In November 2006, Prexige received marketing approval for all European Union countries through a common procedure called MRP. However, in August 2007, Prexige was withdrawn from the market in Australia following 8 serious liver adverse events, including 2 deaths and 2 liver transplants.[3] On September 27, 2007, the US Food and Drug Administration issued a not approvable letter for lumiracoxib, requiring additional safety data.[4] Canada withdrew Prexige (approved at 100 mg dose only) in October 2007.[5] Several European Union countries followed suit in November 2007.[6]

The FDA rejected Prexige as a trade name for lumiracoxib in 2003. Prexede was suggested as an alternative, but the FDA Division of Medication Errors and Technical Support (DMETS) subsequently recommended against it as well.[7]

Withdrawal from market

On August 11, 2007, Australia’s Therapeutic Goods Administration (TGA, the national agency responsible for regulation of pharmaceuticals) cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure.[8]

According to the TGA’s Principal Medical Adviser, Dr Rohan Hammett, as of 10 August 2007 the TGA had received 8 reports of serious adverse liver reactions to the drug, including two deaths and two liver transplants.

“The TGA and its expert advisory committee, the Adverse Drug Reactions Advisory Committee (ADRAC), have urgently investigated these reports. ADRAC has today recommended the cancellation of the registration of Lumiracoxib due to the severity of the reported side effects associated with this drug,” Dr Hammett said.

“The TGA has taken this advice to cancel the registration of Lumiracoxib in order to prevent further cases of severe liver damage.

“It seems that the longer people are on the medicine, the greater the chance of liver injury. The TGA is, therefore, advising people to stop taking the Lumiracoxib immediately and to discuss alternative treatments with their doctor,” Dr Hammett said.[9]

New Zealand has followed suit with Australia in recalling Prexige.[10]

On October 3, 2007, Health Canada requested sales of Prexige to stop. Novartis has agreed to the request and has taken steps to do so.[11] On December 13, 2007, the European Medicines Agency recommended the withdrawal for Prexige from all EU markets.[12]

On January 17, 2008, the Philippines Department of Health ordered Novartis Healthcare Phils. Inc. (Novartis) to remove (recall) all lumiracoxib from local drug stores in 2 weeks due to the harmful effects of the drug (potential serious liver-related side effects, hepatotoxicity or malfunction of the lungs).[13]

On July 22, 2008, The Brazilian National Health Surveillance Agency ordered the withdrawal of 100 mg formulations of lumiracoxib and suspended marketing of the 400 mg formulation for 90 days,[14] after a three-year safety review found a marked increase in adverse event reports; 35% of lumiracoxib-associated adverse events reported worldwide between July 2005 and April 2008 were found to have occurred in Brazil.[15] Lumiracoxib was definitively withdrawn from the Brazilian market on October 3, 2008.[16]

On November 12, 2008, INVIMA, the Colombian National Institute for Food and Drug Surveillance ordered the withdrawal of all presentations of lumiracoxib (Prexige), due to the international reports on hepatotoxicity.

 

 

MECHANISM

 

 

 

Synthesis

 

 

 

The partial reduction of 4-methylanisole (I) with sodium in liquid ammonia / THF / ethanol gives the enol ether (II), which is condensed with 2-chloro-6-fluoroaniline (III) by means of TiCl4 in chlorobenzene / THF to yield the imine (IV), which, without isolation, is aromatized with I2 in AcOH / THF to provide N- (2-chloro-6-fluorophenyl) -N- (4-methylphenyl) amine (V). The acylation of ( V) with 2-chloroacetyl chloride (VI) at 90 C affords the 2-chloroacetamide (VII), which is cyclized by means of AlCl3 by heating at 160? C to afford 1- (2-chloro-6-fluorophenyl) -5 -methylindolin-2-one (VIII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol / water and acidified with 1N HCl. Alternatively, the intermediate N- (2-chloro-6-fluorophenyl) -N- (4- methylphenyl) amine (V) can also be obtained by condensation of 2-chloro-N- (4-methylphenyl) acetamide (IX) with 2-chloro-6-fluorophenol (X) by means of K2CO3 in isopropanol to yield 2- ( 2-chloro-6-fluorophenoxy) -N- (4-methylphenyl) acetamide (XI), which is treated with MeONa in methanol to obtain the target secondary amine (V).
WO 0123346
The reduction of 2-iodo-5-methylbenzoic acid (I) with BH3/THF in THF gives 2-iodo-5-methylbenzyl alcohol (II), which is treated with refluxing 48% HBr to yield the benzyl bromide (III). Reaction of (III) with NaCN in ethanol/water afford the phenylacetonitrile (IV), which is hydrolyzed with NaOH in refluxing EtOH/water to provide the phenylacetic acid (V). Reaction of (V) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VI), which is treated with dimethylamine in diethyl ether/THF to yield 2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide (VII). Condensation of (VII) with 2-chloro-6-fluoroaniline (VIII) by means of Cu powder, Cu2I2 and K2CO3 in refluxing xylene affords 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]-N,N-dimethylacetamide (IX), which is finally hydrolyzed with NaOH in refluxing butanol/water.
The reduction of 2-iodo-5-methylbenzoic acid (I) with BH3/THF in THF gives 2-iodo-5-methylbenzyl alcohol (II), which is treated with refluxing 48% HBr to yield the benzyl bromide (III). Reaction of (III) with NaCN in ethanol/water afford the phenylacetonitrile (IV), which is hydrolyzed with NaOH in refluxing EtOH/water to provide the phenylacetic acid (V). Reaction of (V) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VI), which is treated with dimethylamine in diethyl ether/THF to yield 2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide (VII). Condensation of (VII) with 2-chloro-6-fluoroaniline (VIII) by means of Cu powder, Cu2I2 and K2CO3 in refluxing xylene affords 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]-N,N-dimethylacetamide (IX), which is finally hydrolyzed with NaOH in refluxing butanol/water.
JP 2001514244; US 6291523; WO 9911605

References

  1. Shi, S; Klotz, U (March 2008). “Clinical use and pharmacological properties of selective COX-2 inhibitors.”. European Journal of Clinical Pharmacology 64 (3): 233–52.doi:10.1007/s00228-007-0400-7. PMID 17999057.
  2.  Tacconelli S, Capone ML, Patrignani P (2004). “Clinical pharmacology of novel selective COX-2 inhibitors”. Curr Pharm Des 10 (6): 589–601. doi:10.2174/1381612043453108.PMID 14965322.
  3.  Urgent medicine recall – Lumiracoxib (PREXIGE)
  4.  http://hugin.info/134323/R/1156327/223186.pdf
  5.  Withdrawal of Market Authorization for Prexige
  6.  Media releases
  7.  http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_33_GG-FDA-Tab-U.pdf
  8.  Medicines Regulator cancels registration of anti inflammatory drug, Lumiracoxib, Therapeutic Goods Administration, 11 August 2007. Retrieved on 2007-08-11
  9.  http://www.tga.gov.au/media/2007/070811-lumiracoxib.htm
  10.  “NZ regulators ban arthritis drug”. The New Zealand Herald. 21 August 2007. Retrieved 12 September 2011.
  11.  http://www.novartis.ca/downloads/en/letters/prexige_fact_20071003_e.pdf
  12.  Press release: European Medicines Agency recommends withdrawal of the marketing authorisations for lumiracoxib-containing medicines, 13 December 2007
  13.  Abs-Cbn Interactive, DOH recalls lumiracoxib, sets two-week deadline
  14.  “Anvisa cancela registro do Prexige; consumidor deve substituir medicamento”. Folha de S. Paulo (in Portuguese). July 22, 2008. Retrieved 2008-07-22.
  15.  “Anvisa cancela registro do antiinflamatório Prexige” (Press release) (in Portuguese). Anvisa. July 22, 2008. Retrieved 2008-07-22.
  16.  “Anvisa suspende venda e uso de 2 antiinflamatórios” (in Portuguese). Terra. October 3, 2008. Retrieved 2008-10-03.

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DR ANTHONY CRASTO

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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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