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Valdecoxib

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Valdecoxib.svg
 
 
Valdecoxib3DanJ.gif
 
 
Valdecoxib
CAS Registry Number: 181695-72-7
 4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide
Manufacturers’ Codes: SC-65872
Bextra (Pharmacia & Upjohn)
Molecular Formula: C16H14N2O3S
Molecular Weight: 314.36
 
Percent Composition: C 61.13%, H 4.49%, N 8.91%, O 15.27%, S 10.20%
Properties: Crystals, mp 155-157°. Soly at 25°(mg/ml): water 10 (pH 7.0). Sol in methanol, ethanol; freely sol in organic solvents and alkaline (pH = 12) aqueous solns.
Melting point: mp 155-157°
Therap-Cat: Anti-inflammatory; analgesic

 

Valdecoxib is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, and painfulmenstruation and menstrual symptoms. It is a cyclooxygenase-2 selective inhibitor.

Valdecoxib was manufactured and marketed under the brand name Bextra by G. D. Searle & Company. It was approved by the United States Food and Drug Administration on November 20, 2001,[1] and was available by prescription in tablet form until 2005, when it was removed from the market due to concerns about possible increased risk of heart attack and stroke. The prodrugparecoxib is available in many countries.

 

Uses until 2005

In the United States, the Food and Drug Administration (FDA) approved valdecoxib for the treatment of osteoarthritis, adultrheumatoid arthritis, and primary dysmenorrhea.[2]

Valdecoxib was also used off-label for controlling acute pain and various types of surgical pain.[2]

Side-effects and withdrawal from market

On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on recommendation by the FDA, citing an increased risk of heart attackand stroke and also the risk of a serious, sometimes fatal, skin reaction. This was a result of recent attention to prescription NSAIDs, such as Merck’s Vioxx. Other reported side-effects were angina and Stevens–Johnson syndrome.

Pfizer first acknowledged cardiovascular risks associated with Bextra in October 2004. The American Heart Association soon after was presented with a report indicating patients using Bextra while recovering from heart surgery were 2.19 times more likely to suffer a stroke or heart attack than those taking placebos.

In a large study published in JAMA 2006, valdecoxib appeared less adverse for renal (kidney) disease and heart arrhythmia compared to Vioxx, however elevated renal risks were slightly suggested.[3]

2009 settlement for off-label uses promotions

On September 2, 2009, the United States Department of Justice fined Pfizer $2.3 billion after one of its subsidiaries, Pharmacia & UpJohn Company, pled guilty to marketing four drugs including Bextra “with the intent to defraud or mislead.”[4] Pharmacia & UpJohn admitted to criminal conduct in the promotion of Bextra, and agreed to pay the largest criminal fine ever imposed in the United States for any matter, $1.195 billion.[5] A former Pfizer district sales manager was indicted and sentenced to home confinement for destroying documents regarding the illegal promotion of Bextra.[6][7] In addition, a Regional Manager pled guilty to distribution of a mis-branded product, and was fined $75,000 and twenty-four months on probation.[8]

The remaining $1 billion of the fine was paid to resolve allegations under the civil False Claims Act case and is the largest civil fraud settlement against a pharmaceutical company. Six whistle-blowers were awarded more than $102 million for their role in the investigation.[9] Former Pfizer sales representative John Kopchinski acted as a qui tam relator and filed a complaint in 2004 outlining the illegal conduct in the marketing of Bextra.[10] Kopchinski was awarded $51.5 million for his role in the case because the improper marketing of Bextra was the largest piece of the settlement at $1.8 billion.[11]

 

Assay of Valdecoxib[13]

Several HPLC-UV methods have been reported for valdecoxib estimation in biological samples like human urine,[14] plasma,.[15][16] Valdecoxib has analytical methods for bioequivalence studies,[17][18] metabolite determination,[19][20][21] and estimation of formulation,[22] HPTLC method for simultaneous estimation in tablet dosage form.[23]

Brief background information

Salt ATC Formula MM CAS
M01AH03 C 16 H 14 N 2 O 3 S 314.37 g / mol 181695-72-7
Systematic (IUPAC) name
4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide
Clinical data
Trade names Bextra
Pregnancy cat. C (AU) May cause premature closure of the ductus arteriosus
Legal status Prescription Only (S4) (AU)Withdrawn in U.S., EU, Canada& parts of Asia
Routes Oral
Pharmacokinetic data
Bioavailability 83%
Protein binding 98%
Metabolism Hepatic (CYP3A4 and 2C9involved)
Half-life 8 to 11 hours
Excretion Renal
Identifiers
CAS number 181695-72-7 
ATC code M01AH03
PubChem CID 119607
DrugBank DB00580
ChemSpider 106796 Yes
UNII 2919279Q3W Yes
KEGG D02709 Yes
ChEBI CHEBI:63634 
ChEMBL CHEMBL865 Yes
Chemical data
Formula C16H14N2O3S 
Mol. mass 314.364 g/mol

 

 

Using

  • anti-inflammatory
  • antirheumatic
  • COX-2 inhibitor

Classes of substances

  • Benzenesulfonamide (s -imidy), as well as their derivatives
    • Isoxazoles

Synthesis pathway

Synthesis a)

 

Synthesis

Valdecoxib Rxn.png

Source:[12]

 

 

 

Deoxybenzoin (I) is converted to the corresponding oxime (II) by treatment with NH2OH稨Cl under basic conditions either with sodium acetate in aqueous ethanol or in toluene in presence of potassium hydroxide in absolute ethanol. Deprotonation of the oxime under nitrogen with 2eq of butyllithium in THF followed by cyclization in ethyl acetate or acetic anhydride affords isoxazoline (III). Finally, treatment of (III) with cold chlorosulfonic acid followed by reaction of the intermediate sulfonyl chloride with aqueous ammonia affords the desired product.

J Med Chem2000,43,(5):775

 

 

 

 

Trade Names

Country Trade name Manufacturer
Germany Bextra Pharmacia
USA – “- – “-
Ukraine No No

Formulations

  • Tablets of 10 mg, 20 mg

 

Valdecoxib is chemically designated as 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide and is a diaryl substituted isoxazole.

The empirical formula for valdecoxib is C16H14N2O3S, and the molecular weight is 314.36. Valdecoxib is a white crystalline powder that is relatively insoluble in water (10 µg/mL) at 25° C and pH 7.0, soluble in methanol and ethanol, and freely soluble in organic solvents and alkaline (pH=12) aqueous solutions.

BEXTRA (valdecoxib) Tablets for oral administration contain either 10 mg or 20 mg of valdecoxib. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium,magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide

 ………………………

NMR

Links

  • Talley, JJ et al .: J. Med. Chem. (JMCMAR) 43, 775-777 (2000).
  • US 5,859,257 (GD Searle; 12.1.1999; USA-prior. 13.2.1995).

Literature References:

Selective cyclooxygenase-2 (COX-2) inhibitor. Active metabolite of parecoxib, q.v. Prepn: J. J. Talley et al., WO 9625405 (1996 to Searle); eidem, US 5633272 (1997); and activity: eidem, J. Med. Chem. 43, 775 (2000).

Chromatographic determn of purity: D. A. Roston et al., J. Pharm. Biomed. Anal. 26, 339 (2001).

Gastrointestinal tolerability study: G. M. Eisen et al., Aliment. Pharmacol. Ther. 21, 591 (2005).

Clinical trial in hip arthroplasty: F. Camu et al., Am. J. Ther.9, 43 (2002).

Clinical comparison with oxycodone/acetominophen in dental pain: S. E. Daniels et al., J. Am. Dent. Assoc. 133, 611 (2002).

Clinical trial in migraine: D. Kudrow et al., Headache 45, 1151 (2005).

Review of clinical experience: M. Goldman, S. Schutzer, Formulary 37, 68-77 (2002); of clinical efficacy and safety: G. P. Joshi, Expert Rev. Neurother. 5, 11-24 (2005).

References

  1. Jump up^ Thomson Micromedex. “Valdecoxib. U.S. FDA Drug Approval.” Last accessed June 8, 2007.
  2. ^ Jump up to:a b “Pfizer to pay $2.3 billion to resolve criminal and civil health care liability relating to fraudulent marketing and the payment of kickbacks”. Stop Medicare Fraud, US Dept of Health & Human Svc, and of Justice. Retrieved 2012-07-04.
  3. Jump up^ “Adverse Effects of Cyclooxygenase-2 Inhibitors on Renal and Arrhythmia Events: Meta-Analysis of Randomized Trials”, (JAMA 2006, by Zhang JJ, Ding EL, Song Y.).
  4. Jump up^ http://news.bbc.co.uk/2/hi/business/8234533.stm Pfizer agrees record fraud fine
  5. Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/Sept2009/PharmaciaPlea.html
  6. Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/Mar2009/FarinaconvictionPR.html
  7. Jump up^ http://industry.bnet.com/pharma/10002882/pfizers-off-label-bextra-team-were-called-the-highlanders/
  8. Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/June2009/HollowayMarySentencingPR.html
  9. Jump up^ http://www.fbi.gov/pressrel/pressrel09/justice_090209.htm
  10. Jump up^ http://www.phillipsandcohen.com/CM/NewsSettlements/NewsSettlements536.asp
  11. Jump up^ http://www.phillipsandcohen.com/CM/NewsSettlements/NewsSettlements531.asp
  12. Jump up^ Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. (2000). “4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, Valdecoxib:  A Potent and Selective Inhibitor of COX-2”. Journal of Medicinal Chemistry 43 (5): 775–777. doi:10.1021/jm990577v.PMID 10715145. edit
  13. Jump up^ Prafulla Kumar Sahu and M. Mathrusri Annapurna, Analytical method development by liquid chromatography, LAP Lambert Academic Publisher, Germany, 2011 ISBN 3-8443-2869-6.
  14. Jump up^ Zhang J Y, Fast D M and Breau A P, J Chromatogr B Analyt Technol Biomed Life Sci., 2003, 785(1), 123-134
  15. Jump up^ Ramakrishna N V S, Vishwottam K N; Wishu S and Koteshwara M, J Chromatogr B Analyt Technol Biomed Life Sci., 2004, 802(2), 271.
  16. Jump up^ Sane R T, Menon S, Deshpande A Y and Jain A, Chromatogr., 2005, 61(3-4), 137-141.
  17. Jump up^ Prafulla Kumar Sahu*, K. Ravi Sankar and M. Mathrusri Annapurna, Determination of Valdecoxib in human plasma using Reverse Phase HPLC”, E-Journal of Chemistry, 2011, 8(2), 875-881.
  18. Jump up^ Mandal U, Jayakumar M, Ganesan M, Nandi S, Pal T K, Chakraborty M K, Roy Chowdhary A. and Chattoraj T K, Indian Drugs, 2004, 41, 59.
  19.  Zhang J.Y, Fast D.M and Breau, A.P, J Pharm Biomed Anal., 2003, 33, 61.
  20.  Werner U, Werner D, Hinz B, Lanbrecht C and Brune K, J Biomed Chromatogr., 2004, 19, 113.
  21.  Zhang J V, Fast D M and Breau A P, J Chromatogr B Anal Technol Biomed Life Sci., 2003, 785, 123.
  22.  Sutariya V B, Rajashree M, Sankalia M G. and Priti P, Indian J Pharm Sci., 2004, 93, 112.
  23. J Gandhimathi M, Ravi T K, Shukla Nilima and Sowmiya G, Indian J Pharm Sci., 2007, 69(1), 145-147.

External links[edit]

 

 


1 Comment

  1. Dr.Saiganesh says:

    Interestingly the hemiacetal ( dihydroisoxazole ) is very stable and doen not get get dehydrated under simple acidic conditions like HCl, Acetic acid etc. It gets dehyderated only under strongly acidic conditions like sulphuric acid or chlorsulphonicacid. Another point is for chlorosulfonation followed by amidation excess of Chlorsulfonic acid is required . Also a regio isomer formationis inevitable

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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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