COXIB SERIES

COXIB SERIES

1  CELECOXIB
2. CIMICOXIB
3. TILMACOXIB
4. APRICOXIB
5 LUMIRACOXIB
6 ROFECOXIB
7 VALDECOXIB
8
9

WILL BE UPDATED

Drug spotlight, Celecoxib from G. D. Searle Company

1 Vote

CELECOXIB

169590-42-5

Celecoxib  is a sulfonamide non-steroidal anti-inflammatory drug (NSAID) and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis. It is marketed by Pfizer. It is known under the brand name Celebrex or Celebra for arthritis and Onsenal for polyps. Celecoxib is available by prescription in capsule form.

Celecoxib was discovered developed by G. D. Searle & Company and was approved by the FDA on December 31, 1998. It was co-promoted byMonsanto Company (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia, from which the Medical Research Division was acquired by Pfizer, giving Pfizer ownership of Celebrex. The drug was at the core of a major patent dispute that was resolved in Searle’s favor (later Pfizer) in 2004. In University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004), the University of Rochester claimed that United States Pat. No. 6,048,850 (which claimed a method of inhibiting COX-2 in humans using a compound, without actually disclosing what that compound might be) covered drugs such as celecoxib. The court ruled in favor of Searle, holding in essence that the University had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.

After the withdrawal of rofecoxib (Vioxx) from the market in September 2004, Celebrex enjoyed a robust increase in sales. However, the results of the APC trial in December of that year raised concerns that Celebrex might carry risks similar to those of Vioxx, and Pfizer announced a moratorium on direct-to-consumer advertising of Celebrex soon afterwards. After a significant drop, sales of Celebrex have recovered, and reached $2 billion in 2006.[6] Pfizer resumed advertising Celebrex in magazines in 2006, and resumed television advertising in April 2007 with an unorthodox, 2 1⁄2-minute advertisement which extensively discussed the adverse effects of Celebrex in comparison with other anti-inflammatory drugs. The ad drew criticism from the consumer advocacy group Public Citizen, which called the ad’s comparisons misleading. Pfizer has responded to Public Citizen’s concerns with assurances that they are truthfully advertising the risk and benefits of Celebrex as set forth by the FDA.

In late 2007, Pfizer released another U.S. television ad for Celebrex, which also discussed celecoxib’s adverse effects in comparison with those of other anti-inflammatory drugs.

Daniel L. Simmons of Brigham Young University, who discovered the COX-2enzyme, is suing Pfizer to be credited with discovery of the technique in 1989 that eventually led to the drug, and for $1 billion USD. The company has made about $30 billion from the drug as of 2006. A settlement was finally reached in April 2012.

Celecoxib is licensed for use in osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, ankylosing spondylitis and to reduce the number of colon and rectal polyps in patients with familial adenomatous polyposis. It was originally intended to relieve pain while minimizing the gastrointestinal adverse effects usually seen with conventional NSAIDs. In practice, its primary indication is in patients who need regular and long term pain relief; there is probably no advantage to using celecoxib for short term or acute pain relief over conventional NSAIDs, except in the situation where non-selective NSAIDs or aspirin cause cutaneous reactions (urticaria or “hives”). In addition, the pain relief offered by celecoxib is similar to that offered by paracetamol (acetaminophen).

Synthesis

The synthesis of celecoxib was first described in 1997 by a team of researchers at Searle Research and Development. Celecoxib is synthesized by a Claisen condensation reaction of an acetophenone with N-(trifluoroacetyl)imidazole catalyzed by the strong base, sodium bis(trimethylsilyl)amide to produce a 1,3-dicarbonyl adduct. Condensation of the diketone with (4-sulfamoylaphenyl)hydrazine produces the 1,5-diarylpyrazole drug moiety.

……………………………….

CELECOXIB

169590-42-5
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Celecoxib)

PAPER

http://pubs.acs.org/doi/abs/10.1021/op800158w

An Improved and Scalable Process for Celecoxib: A Selective Cyclooxygenase-2 Inhibitor

Anumula Raghupathi Reddy ET AL

Department of Research and Development, Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, R R Dist-500 072, A.P., India

Org. Process Res. Dev., 2009, 13 (1), pp 98–101

DOI: 10.1021/op800158w
E-mail: prataprp@ drreddys.com. Fax: 914044346285. Telephone: 9989997176

HPLC 99.97%; regioisomer 0.03%; DSC 162.14 °C; Heavy metals <10 ppm;

M/S m/z 382 M+ + H;

IR (KBr) cm−1 3341, 3235 (N−H);

1H NMR, (DMSO-d6) δ 7.89 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H); 7.52 (s, NH2); 7.22 (m, 4H); 7.17 (s, 1H); 2.32 (s, 3H);

13C NMR (DMSO-d6) δ 20.7, 37.4, 106.1, 121.5, 125.3, 125.9, 126.8, 128.7, 129.4, 139.1, 141.1, 142.2, 144.0, 145.2, 267.4;

Anal. Calcd for C17H14F3N3O2S: C 53.53, H 3.69, N 11.01, S 8.39. Found: C 53.50, H 3.70, N 11.01, S 8.44.

An improved, scalable and commercially viable process is developed for an active pharmaceutical ingredient, celecoxib.

HPLC Conditions:

Column: Kromasil 100 C18, 250 mm × 4.6 mm × 5 μm

Wavelength: 258 nm

Flow: 0.8 mL/min

Temperature: 25 °C

Injection load: 10 μL

Run time: 60 min

Mobile phase A: buffer (1.36 g potassium dihydrogen phosphate and 0.22 g octane-1-sulfonic acid sodium salt in 1 L of milli-Q water. pH adjusted to 3.3 with dilute H3PO4)

Mobile phase B: acetonitrile and water in the ratio of 7:3

Gradient program: time (min): 0 8 20 30 42 45 60

% of mobile phase A: 50 50 10 5 5 50 50

% of mobile phase B: 50 50 90 95 95 50 50

Retention time of celecoxib: 29.2 min

Retention time of regioisomer: 30.9 min

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Celecoxib extraction
Celecoxib was extracted from Celebra™ 100
mg and 200 mg capsules. Ten capsules were
crushed to fine powder, using agate mortar and
pestle, transferred to a 50 ml volumetric flask
and diluted to volume with methanol. The solution
was shaked for 5 min and filtered. The
residue was recrystallized from acetonitrile after
evaporation of the solvent in a water bath at 50
°C, under a stream of nitrogen.

Thin layer Chromatography (TLC) In this procedure it was used silica gel 60 F254 plates (20 x 20 cm) with a thickness of 0.25 mm. All plates used were commercially prepared by MERCK (lot # 040422153). The mobile phase used to develop the system consisted of chloroform-ethyl acetate-ether (10:5:1, v/v/v). Just in order to verify the selectivity of the proposed system, another COX-2 inhibitor (rofecoxib) with similar properties was used. 20 µl of celecoxib reference substance and extracted from tablets and rofecoxib solutions (50 µg.ml–1) were spotted on the TLC plates, and transferred to a developing tank containing the mobile phase. The plate was then examined under UV light (254 and 365 nm).

Thin-layer chromatography One of the most effective screening methods is the thin-layer chromatography (TLC), which is the simplest of all the widely used chromatographic methods to perform. In the determination of this method, different chromatography systems were tested and analyzed according to the classification proposed by Moffat 13, which divide the drugs in three categories: acid, basic and neutrals based on their polarity and acid characteristics. This procedure is important in
order to increase the information obtained only by changing the mobile phase, and thus resulting in a significant change in selectivity. These chromatographic systems consisted of mixtures of the following solvents: chloroformacetonitrile, ethyl acetate, acetone and methanol, in different concentrations. Nevertheless, all the mobile phases tested were not adequate for the proper identification of the drug. With the objective to develop more reliable chromatographic method, a modification in the system tested was proposed, in order to improve the chromatographic resolution. The mobile phase used consisted of chloroform-ethyl acetate-ether (10:5:1 v/v/v). The system was chosen due to its sensitivity, simplicity and efficacy
The preference to use commercially prepared silica gel plates was due to its durability and homogeneity of the absorbent layer. A sample solution of the working standard and the drug sample (50 (µg ml–1) were spotted onto a silica gel plate with a micropipette and the chromatogram was developed by placing the plate in a tank containing the mobile phase. Following development the individual solute spots were identified under UV lamp (254 and 365 nm). The spots in the drug sample and the working standard presented similar Rf values. The Rf value obtained for drug sample and the working standard were 0.45 and for rofecoxib 0.32.

NMR

The spectrum shown in Figure 3 possesses two characteristic sharp singlet peaks at 2.3 and3.3 ppm that belong to the methyl and sulfonamide protons of celecoxib. The spectrum also reveals peaks from 7.3 to 7.9, which is due to the protons of aromatic groups. The characteristics peaks from the working standard agree well with those observed in the samples, considering the fact that a constant shift is observed in all peaks 11, 12.

UV

IR
1150 – 1350 S = O stretching (sulfonamide group)
1550 – 1600 N – H stretching
3300 – 3500 NH2 stretching

1H NMR PREDICT

13 C NMR

(4) (a) Matsuo, M.; Tsuji, K.; Konishi, N.; Nakamura, K. EP patent 0,418,845, A1, 1990. (b) Matsuo, M.; Tsuji, K.; Konishi, N.; Ogino, T. EP patent 0,554,829, A1, 1993. (c) Nishiwaki, T. Bull. Chem. Soc. Jpn. 1969, 42, 3024. (d) Soliman, R.; Feid-allah, H. J. Pharm. Sci. 1980, 70, 602. (e) Wright, J. B.; Dulin, W. E.; Markillie, J. H. J. Med. Chem. 1963, 7, 102. (f) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med. Chem. 2001, 44, 3039. (g) Szabo, G.; Fischer, J.; Kis-Varga, A.; Gyires, K. J. Med. Chem. 2008, 51, 142. (h) Oh, L. M. Tetrehedron Lett. 2006, 47, 7943.

(5) Talley, J. J.; Penning, T. D.; Collins, P. W.; Rogier, D. J.; Malecha, J. W.; Miyashiro, J. M.; Bertenshaw, S. R.; Khanna, I. K.; Graneto, M. J.; Rogers, R. S.; Carter, J. S. US patent 5,466,823, 1995.

(6) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347.

7 Talley, J. J.; Penning, T. D.; Collins, P. W.; Rogier, D. J.; Malecha, J. W.; Miyashiro, J. M.; Bertenshaw, S. R.; Khanna, I. K.; Graneto, M. J.; Rogers, R. S.; Carter, J. S.; Docter, S. H.; Yu, S. S. US patent 6,586,603, B1, 2003.

(8) (a) O′ Shea, P. ; Tillyer, R. D. ; Wang, X. ; Clas, S. D. ; Dalton, C. US patent 6,150,534, 2000. (b) O′ Shea, P. ; Tillyer, R. D. ; Wang, X. ; Clas, S. D. ; Dalton, C. US patent 6,232,472, 2001.

(9) (a) Zhi, B. ; Newaz, M. US patent 5,,892,053, 1999. (b) Zhi, B. ; Newaz, M. US patent 5,910,597, 1999.

10(a) Letendre, L. J.; McGhee, W. D.; Snoddy, C.; Klemm, G.; Graud, H. T. US patent 7,141,678, 2006. (b) Letendre, L. J.; McGhee, W. D.; Snoddy, C.; Klemm, G.; Graud, H. T. US patent 2007/0,004, 924 A1, 2007.
(11) ICH harmonized tripartite guideline, Impurities in New Drug Substances Q3A (R2), current step 4 version dated 25 October2006.
(12) Ahlstrom, M. M.; Ridderstrom, M.; Zamora, I.; Luthman, K. J. Med. Chem. 2007, 50, 4444. (13) Soliman, R. J. Med. Chem. 1979, 22, 321.

SYNTHESIS

  +GIVES……..CELECOXIB

EUCLISES PHARMACEUTICALS, INC.; MARTINEZ, Eduardo, J.; TALLEY, John, J.; JEROME, Kevin, D.; BOEHM, Terri, L. Patent: WO2014/12074 A2, 2014 ; Location in patent: Paragraph 00209; 00210

2

+

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Reddy, Anumula Raghupathi; Sampath, Alla; Goverdhan, Gilla; Yakambaram, Bojja; Mukkanti, Kagga; Reddy, Padi Pratap Organic Process Research and Development, 2009 , vol. 13, # 1 p. 98 – 101

3
Prabhakaran, Jaya; Underwood, Mark D.; Parsey, Ramin V.; Arango, Victoria; Majo, Vattoly J.; Simpson, Norman R.; Van Heertum, Ronald; Mann, J. John; Kumar, J.S. Dileep Bioorganic and Medicinal Chemistry, 2007 , vol. 15, # 4 p. 1802 –

4
Li, Feng; Nie, Jing; Sun, Long; Zheng, Yan; Ma, Jun-An Angewandte Chemie – International Edition, 2013 , vol. 52, # 24 p. 6255 – 6258

5
Synlett, , vol. 1997, # 4 p. 375 – 377

6Tetrahedron Letters, , vol. 52, # 45 p. 6000 – 6002

7

Bioorganic and Medicinal Chemistry Letters, , vol. 21, # 22 p. 6636 – 6640

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2 CIMICOXIB

Cimicoxib

UR-8880,

CAS 265114-23-6,

Molecular Formula: C₁₆H₁₃ClFN₃O₃S

Molecular Weight: 381.809123

Uriach (Originator)

4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl]benzenesulfonamide

IN PHASE 2

Cimicoxib (trade name Cimalgex) is a non-steroidal anti-inflammatory drug (NSAID) used in veterinary medicine to treat dogs for pain and inflammation associated with osteoarthritis and for the management of pain and inflammation associated with surgery.^[1] It acts as a COX-2 inhibitor.

Cimicoxib is a selective COX-2 inhibitor being developed by Affectis as a treatment for depression and schizophrenia. If approved, Cimicoxib would be the first drug in decades to treat depression by a new mechanism of action

Cimicoxib, an imidazole derivative, is a selective cyclooxygenase-2 (COX-2) inhibitor. The product was in phase II development at Affectis Pharmaceuticals for the oral treatment of major depression, however, no recent development have been reported. Originally developed by Uriach, the compound was acquired by Palau Pharma, a spin-off created by Uriach in November 2006.

In 2007, Palau Pharma licensed global rights to cimicoxib to Affectis Pharmaceuticals for all CNS indications. Palau had been clinically evaluating the compound for the treatment of osteoarthritis, pain and rheumatoid arthritis, however, no recent development has been reported for these indications. The compound holds potential for the treatment of schizophrenia.

Treatment of 4-(acetylamino)phenylsulfonyl chloride (I) with tert-butylamine yields sulfonamide (II), which on deprotection with potassium hydroxide gives amine (III). Reaction of compound (III) with 4-methoxy-3-fluorobenz-aldehyde gives imine (IV), which is cyclized with tosylmethyl isocyanide to afford imidazole (V). Regioselective chlorination of compound (V) with N-chlorosuccinimide (NCS) to afford the chloroimidazole (VI) and then deprotection of the sulfonamide group of (VI) yields cimicoxib in 40% overall yield.

EP 1122243; JP 2002527508; WO 0023426, ES 2184633; WO 0316285

.....................................

http://www.google.com/patents/EP1424329A1?cl=en

EXAMPLE 1

4-Amino-N- tert -butylbenzenesulfonamide Method A:

• [0031]
  

a) N-tert-Butyl-4-nitrobenzenesulfonamide

• [0032]
  To a solution of tert-butylamine (0.47 L, 6.4 mol) in THF (0.55 L) is slowly added, at 0 °C, a solution of 4-nitrobenzenesulfonyl chloride (50 g, 0.23 mol) in THF (0.55 L) and the resulting mixture is stirred for 24 h at room temperature. The solvent is removed and the residue is taken up in a CHCl₃/0.5 N HCl mixture, the layers are separated and the aqueous phase is extracted with CHCl₃. The combined organic extracts are washed with H₂O and brine and dried over MgSO₄. The solvent is removed, yielding 56.3 g of a yellowish solid which is directly used in the next reaction (yield: 97%).
  Mp: 105-109°C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.29 (s, 9 H), 5.07 (s, 1 H), 8.13 (d, J = 9 Hz, 2 H), 8.39 (d, J = 9 Hz, 2 H).

b) Title compound

• [0033]
  A solution of N-tert-butyl-4-nitrobenzenesulfonamide (10.0 g, 39 mmol) in EtOH (100 mL) is stirred for 48 h under a H₂ atmosphere in the presence of 10% Pd/C (1.50 g). The resulting mixture is filtered and concentrated to give the desired product as a slightly-coloured solid (8.7 g, yield: 98%).
  Mp: 127 °C; ¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 1.19 (s, 9 H), 3.74 (s, CD₃OD + 1 H), 6.93 (d, J = 9 Hz, 2 H), 7.66 (d, J = 9 Hz, 2 H).

Method B:

• [0034]
  

a) 4-Acetylamino-N-tert-butylbenzenesulfonamide

• [0035]
  To a suspension of 4-acetylaminobenzenesulfonyl chloride (10 g, 43 mmol) in DME (103 mL) is added, at 0 °C, tert-butylamine (9 mL, 86 mmol) in DME (103 mL). Next, the reaction mixture is stirred for 4 h at reflux. The solvent is removed and CHCl₃ is added. The resulting suspension is filtered and the solid is washed with CHCl₃, H₂O and Et₂O. The solid obtained is dried in vacuo to give 8.0 g of the product as a white solid (yield: 68%).
  Mp: 200-201 °C; ¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 1.15 (s, 9 H), 2.12 (s, 3 H), 4.21 (s, 2H + CD₃OD), 7.66 (d, J = 9 Hz, 2 H), 7.75 (d, J = 9 Hz, 2 H).

b) Title compound

• [0036]
  A solution of 4-acetylamino-N-tert-butylbenzenesulfonamide (8.0 g, 29.6 mmol), KOH (8.30 g, 148 mmol), H₂O (6 mL) and MeOH (24 mL) is heated at 100°C for 2 h. H₂O (24 mL) is added and the mixture is heated for two more hours. It is allowed to cool, H₂O is added and it is brought to pH 8 with 1N HCl. It is then extracted with EtOAc, dried over Na₂SO₄ and the solvent is removed, to give 6.0 g of the product as a white solid (yield: 89%).

EXAMPLE 2 N- tert -Butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide

• [0037]
  
• [0038]
  A mixture of 4-amino-N-tert-butylbenzenesulfonamide (52.3 g, 0.23 mol, obtained in example 1), 3-fluoro-4-methoxybenzaldehyde (35.3 g, 0.23 mol) and toluene (2.5 L) is heated at reflux in a Dean-Stark for 24 h. The solvent is removed, yielding 83.5 g of the title compound (yield: quantitative).
  Mp: 129-131 °C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.23 (s, 9 H), 3.98 (s, 3 H), 4.65 (s, 1 H), 7.04 (t, J = 8.1 Hz, 1 H), 7.21 (d, J = 6.7 Hz, 2 H), 7.58 (m, 1 H), 7.73 (dd, J_H-F = 11.8 Hz, J = 2 Hz, 1 H), 7.90 (d, J = 6.7 Hz, 2 H), 8.33 (s, 1 H).

EXAMPLE 3 N-tert-Butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

• [0039]
  
• [0040]
  A mixture of N-tert-butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide (41.5 g, 114 mmol, obtained in example 2), tosylmethylisocyanide (33.22 g, 171 mmol), K₂CO₃ (31.1 g, 228 mmol), DME (340 mL) and MeOH (778 mL) is heated at reflux for 3 h. The solvent is removed and the residue is taken up in a CHCl₃/H₂O mixture and the layers are separated. The aqueous phase is extracted with CHCl₃ and the combined organic extracts are dried over MgSO₄ and concentrated. A crude product is obtained, which is washed with Et₂O several times to give 41.40 g of a creamy solid that is directly used in the next reaction (yield: 90%).
  Mp: 229-232°C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.24 (s, 9 H), 3.89 (s, 3 H), 4.51 (s, 1 H), 6.90 (m, 3 H), 7.23 (s, 1 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.73 (s, 1 H), 7.94 (d, J = 8.7 Hz, 2 H).

EXAMPLE 4 N-tert-Butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

• [0041]
  
• [0042]
  A mixture of N-tert-butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (41.40 g, 103 mmol, obtained in example 3) and acetonitrile (840 mL) is heated at reflux and acetonitrile is added until complete dissolution (200 mL more). Next, N-chlorosuccinimide (15.0 g, 113 mmol) is added and the mixture is refluxed for 24 h. The solvent is removed and the residue is suspended in EtOAc and 1N HCl and is stirred for 10 min. The solid obtained is filtered and washed directly in the filter with 1N HCl, 1N NaOH, saturated NH₄Cl solution, H₂O and Et₂O. A solid is obtained, which is dried in vacuo to give 37.0 g of the product as a creamy solid (yield: 82%).
  Mp: 208-210 °C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.24 (s, 9 H), 3.89 (s, 3 H), 4.51 (s, 1 H), 6.90 (m, 3 H), 7.23 (d, J = 8.7 Hz, 2 H), 7.63 (s, 1 H), 7.92 (d, J = 8.7 Hz, 2 H).

EXAMPLE 5 4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

• [0043]
  
• [0044]
  A mixture of N-tert-butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (37.0 g, 85 mmol, obtained in example 4), concentrated HCl (200 mL) and H₂O (200 mL) is heated at reflux for 3 h. The mixture is allowed to cool and is brought to pH 6 with 6N NaOH. A white precipitate appears, which is collected by filtration and washed with plenty of H₂O and then with CHCl₃. 31 g of the title compound of the example is obtained (yield: 97%), which are recrystallized from acetonitrile.
  Mp: 211-212 °C;
• ¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 3.90 (s, 3 H), 4.16 (s, CD₃OD + 2 H), 6.93 (m, 3 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.73 (s, 1 H), 7.95 (d, J = 8.7 Hz, 2 H).

References

1. "European Public Assessment Report: Cimalgex (cimicoxib)". European Medicines Agency.

23685411	9-1-2013	Detection and quantification of cimicoxib, a novel COX-2 inhibitor, in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology.	Journal of pharmaceutical and biomedical analysis
23710692	6-1-2013	Efficacy and safety of cimicoxib in the control of perioperative pain in dogs.	The Journal of small animal practice
17335184	4-5-2007	NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties.	Journal of medicinal chemistry
15481993	10-21-2004	New water-soluble sulfonylphosphoramidic acid derivatives of the COX-2 selective inhibitor cimicoxib. A novel approach to sulfonamide prodrugs.	Journal of medicinal chemistry
12877584	7-31-2003	Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.	Journal of medicinal chemistry

US2005080084	4-15-2005	Compositions of a cyclooxygenase-2 selective inhibitor and a serotonin-modulating agent for the treatment of central nervous system damage
US2005075341	4-8-2005	Compositions of a cyclooxygenase-2 selective inhibitor and an IKK inhibitor for the treatment of ischemic mediated central nervous system disorders or injury

US2009012307	1-9-2009	Process for the Preparation of 4-(imidazol-1-yl)benzenesulfonamide Derivatives
US2008213376	9-5-2008	Medicament that is Intended for Oral Administration, Comprising a Cyclooxygenase-2 Inhibitor, and Preparation Method Thereof
US7351836	4-2-2008	Method of preparing 4-(imidazol-1-yl)benzenesulphonamide derivatives
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US2005148589	7-8-2005	Compositions of a cyclooxygenase-2 selective inhibitor and a neurotrophic factor-modulating agent for the treatment of central nervous system mediated disorders
US2005113434	5-27-2005	Compositions of a cyclooxygenase-2 selective inhibitor administered under hypothermic conditions for the treatment of ischemic mediated central nervous system disorders or injury
US2005101597	5-13-2005	Compositions of a cyclooxygenase-2 selective inhibitior and a non-NMDA glutamate modulator for the treatment of central nervous system damage
US2005085478	4-22-2005	Compositions of a cyclooxygenase-2 selective inhibitor and a low-molecular-weight heparin for the treatment of central nervous system damage
US2005085479	4-22-2005	Mediated central nervous system compositions of a cyclooxygenase-2 selective inhibitor and a corticotropin releasing factor antagonist for the treatment of ischemic disorders or injury

3 TILMACOXIB

Tilmacoxib

JTE-522, JTP-19605, RWJ-57504,

CAS 180200-68-4,

4-(4-Cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide

4-(4-cyclohexyl-2-methyl-1,3-oxazol-5-yl)-2-fluorobenzenesulfonamide

5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo(4,5)imidazo(1,2a)pyridine-4-N-(2-fluorophenyl)carboxamide

  4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide

Molecular Formula: C₁₆H₁₉FN₂O₃S

Molecular Weight: 338.397063

Japan Tobacco (JT) (Originator)

Tilmacoxib or JTE-522 is a COX-2 inhibitor and is an effective chemopreventive agent against rat experimental liver fibrosis.^[1]

A member of the class of 1,3-oxazoles that is that is 1,3-oxazole which is substituted at positions 2, 4 and 5 by methyl, cyclohexyl, and 3-fluoro-4-sulfamoylphenyl groups, respectively.

...........

4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: Enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522
J Med Chem 2002, 45(7): 1511

http://pubs.acs.org/doi/abs/10.1021/jm010484p

A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.

9d as a white solid:  mp 166−167 °C; ¹H NMR (CDCl₃) δ 1.3−1.5 (m, 3H), 1.6−1.9 (m, 7H), 2.51 (s, 3H), 2.79 (tt, J = 3.7, 11.3 Hz, 1H), 5.11 (s, 2H), 7.36−44 (m, 2H), 7.94 (t, J = 7.9 Hz, 1H). Anal. (C₁₆H₁₉FN₂O₃S) C, H, N.

..................

WO 1996019463 OR http://www.google.com/patents/EP0745596A1?cl=en

Example 2

• [0080]
  Synthesis of 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom)
  Step 10) Cyclohexyl 3-fluorobenzyl ketone (formula (IV'); R'=cyclohexyl, R₁'=3-fluorophenyl)
  

  
• [0081]
  To a solution of tetrakis(triphenylphosphine)palladium (2.00 g) and zinc powder (17.98 g) in 1,2-dimethoxyethane (50 ml) was added a solution of cyclohexanecarbonyl chloride (20.00 g) in 1,2-dimethoxyethane (50 ml) at room temperature under a nitrogen atmosphere. A solution of 3-fluorobenzyl bromide (26.00 g) in 1,2-dimethoxyethane (100 ml) was gradually added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, and at room temperature for 2 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. Then, ethyl acetate (200 ml) was added to the residue, and the mixture was washed with 1N hydrochloric acid, and then with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 29.20 g of an oily crude product.
  Step 16) 2-Cyclohexyl-1-(3-fluorophenyl)-2-oxoethyl acetate (formula (V''); R'=cyclohexyl, R₁'=3-fluorophenyl, R₂'=methyl, Z=oxygen atom)
  

  
• [0082]
  Lead tetraacetate (75.00 g) was added to a solution of the compound (29.20 g) obtained in the above Step 10) in acetic acid (300 ml). The mixture was refluxed under heating for 1.5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=9:1) to give 18.30 g of the title compound as an oil (yield 50%).
  Step 17) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula (XIII); R'=cyclohexyl, R₁'=3-fluorophenyl, R₂=methyl, Z=oxygen atom)
  

  
• [0083]
  A solution of the compound (18.00 g) obtained in the above Step 16) and ammonium acetate (15.00 g) in acetic acid (100 ml) was refluxed under heating for 5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 17.20 g of an oily crude product. Step 15) 5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom)
  

  
• [0084]
  To a solution of the compound (17.00 g) obtained in the above Step 17) in chloroform (80 ml) was added dropwise chlorosulfonic acid (27 ml) with stirring under ice-cooling, and the mixture was heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature, and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
• [0085]
  Aqueous ammonia (28%) was added to a solution of the obtained compound (10.00 g) in tetrahydrofuran (40 ml) with stirring at room temperature, and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (developing solvent; dichloromethane:ethyl acetate=6:1) to give 5.74 g of the title compound (yield 61%).

Example 2'

• [0086]
  The compound of Example 2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom) was synthesized according to another synthetic method.
  Step 11) Cyclohexyl 3-fluorobenzyl ketone oxime (formula (XI); R'= cyclohexyl, R₁'=3-fluorophenyl)
  

  
• [0087]
  To a solution of the compound (353 g) obtained according to a method similar to that of the above Example 2, Step 10) in ethanol (1300 ml) were added hydroxylamine hydrochloride (123 g) and sodium acetate (158 g). The mixture was refluxed under heating for 2 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was recrystallized from n-heptane to give 160 g of the title compound (yield 42%).
  Step 14) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula (XIII); R'=cyclohexyl, R₁'=3-fluorophenyl, R₂=methyl, Z=oxygen atom)
  

  
• [0088]
  Acetic anhydride (95 ml) was dropwise added to a solution of the compound (158 g) obtained in the above Step 11) in acetic acid (900 ml) with stirring at room temperature, and the mixture was refluxed under heating for 7 hours. The solvent was evaporated under reduced pressure and n-heptane was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution, saturated brine and acetonitrile. The solvent was evaporated under reduced pressure to give 119 g of the title compound as an oil.
• [0089]
  Then, the obtained compound (119 g) was reacted in the same manner as in the above Example 2, Step 15) to give a compound of Example 2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom).

Example 3

• [0090]
  Synthesis of 4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonylphenyl, R₂=methyl, Z=oxygen atom)
  Step 15) 4-Cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonylphenyl, R₂=methyl, Z=oxygen atom)
  

  
• [0091]
  To a solution of the compound (17.00 g) obtained in the above Example 2, Step 17) in chloroform (80 ml) was dropwise added chlorosulfonic acid (27 ml) with stirring under ice-cooling. The mixture was heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
• [0092]
  Water (25 ml) was added to the obtained compound (3.66 g). To the mixture were added sodium sulfite (1.42 g) and sodium hydrogencarbonate (1.89 g) successively with stirring at room temperature. The mixture was heated at 70°C for 2 hours. Ethanol (25 ml) and methyl iodide (2.20 g) were added to the mixture, and the mixture was heated at 100°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate.
• [0093]
  The solvent was evaporated under reduced pressure, and the residue was saparated and purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1) to give 0.82 g of the title compound (yield 24%).

References

1. Yamamoto, H., Kondo, M., Nakamori, S., Nagano, H., Wakasa, K., Sugita, Y., Chang-De, J., Kobayashi, S., Damdinsuren, B., Dono, K., Umeshita, K., Sekimoto, M., Sakon, M., Matsuura, N., Monden, M. (2003). "JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis1". Gastroenterology 125 (2): 556–571. doi:10.1016/s0016-5085(03)00904-1. PMID 12891558.

2. 11906292

   3-28-2002

   4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522(1).

   Journal of medicinal chemistry

10406640

7-5-1999

The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor.

Bioorganic & medicinal chemistry letters

 


4 APRICOXIB

APRICOXIB

A COX-2 inhibitor.

MF; C19H20N2O3S

Mol wt: 356.439

CAS: 197904-84-0

CS-701; TG01, R-109339, TG-01 ,TP-1001
TP-2001, Capoxigem, Kymena,  UNII-5X5HB3VZ3Z,

Benzenesulfonamide, 4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]-;

4-[2-(4-Ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide

4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide .

PHASE 2 http://clinicaltrials.gov/search/intervention=Apricoxib

Daiichi Sankyo (innovator)Daiichi Sankyo Co Ltd,

Current developer:  Tragara Pharmaceuticals, Inc.

Apricoxib is an orally bioavailable nonsteroidal anti-inflammatory agent (NSAID) with potential antiangiogenic and antineoplastic activities. Apricoxib binds to and inhibits the enzyme cyclooxygenase-2 (COX-2), thereby inhibiting the conversion of arachidonic acid into prostaglandins. Apricoxib-mediated inhibition of COX-2 may induce tumor cell apoptosis and inhibit tumor cell proliferation and tumor angiogenesis. COX-related metabolic pathways may represent crucial regulators of cellular proliferation and angiogenesis.

R-109339 is a cyclooxygenase-2 (COX-2) inhibitor currently in phase II clinical development at Tragara Pharmaceuticals for the oral treatment of non-small cell lung cancer (NSCLC) and for the treatment of inflammation. Additional phase II clinical trials are ongoing in combination with gemcitabine and erlotinib for the treatment of pancreas cancer. The company had been evaluating R-109339 for the treatment of colorectal cancer, but development for this indication was discontinued for undisclosed reasons. Daiichi Sankyo and Tragara Pharmaceuticals had been conducting phase II clinical trials with the drug candidate for the oral treatment of arthritis and for the treatment of breast cancer, respectively; however, no recent development for this indication has been reported.

COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid, which is derived from the cellular phospholipid bilayer by phospholipase A2. In addition to several other functions, prostaglandins act as messenger molecules in the process of inflammation. The compound is also designed to act against a well-defined cancer pathway that affects several routes of cancer pathogenesis. In preclinical cancer models, R-109339 demonstrated superiority to compounds with similar mechanisms of action and potential for use in combination with cisplatin. Furthermore, the compound demonstrated the ability to inhibit the cachexia and weight loss seen in mouse tumor models.

Apricoxib, (CS-706, 1) 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, a small-molecule, orally active, selective COX-2 inhibitor was discovered by investigators at Daiichi Sankyo in 1996. Clinical studies demonstrated potent analgesic activity and preclinical studies demonstrated good pharmacokinetics, pharmacodynamics and gastrointestinal tolerability. As an anticancer agent, preclinical studies demonstrated efficacy in biliary tract cancer models and colorectal carcinoma, and Recamp et al.

The original synthetic route is outlined below. Though the initial two steps were accomplished with decent yields, the final step of pyrrolidine formation followed by dehydration and dehydrocyanation produced only 3% of 1 as a brown powder. The yield in the last step of the synthesis of the 2-(4-methoxyphenyl) analog, 2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, was 6%, indicating that this synthesis route is problematic.

14   Kimura T, Noguchi Y, Nakao A, Suzuki K, Ushiyama S, Kawara A, Miyamoto M. 799823. EP. 1997:A1.

............................

Synthesis

Bioorg Med Chem Lett. Oct 15, 2011; 21(20): 6071–6073.

Published online Aug 19, 2011. doi:  10.1016/j.bmcl.2011.08.050

SEE AT

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310163/

An efficient synthesis of apricoxib (CS-706), a selective cyclooxygenase inhibitor, was developed using copper catalysed homoallylic ketone formation from methyl 4-ethoxybenzoate followed by ozonolysis to an aldehyde, and condensation with sulphanilamide. This method provided multi-gram access of aprocoxib in good yield. Apricoxib exhibited potency equal to celecoxib at inhibition of prostaglandin E₂ synthesis in two inflammatory breast cancer cell lines.

We envisioned that 7 could be prepared by ozonolysis of homoallylic ketone (8) (Route B). A recent development in the synthesis of homoallylic ketones by Dorr et al. via copper-catalyzed cascade addition of alkenylmagnesium bromide to an ester a²⁴ was examined. Treatment of commercially available methyl 4-ethoxybenzoate with 1-propenylmagnesium bromide (4.0 equiv) in presence of CuCN (0.6 equiv) resulted in 95% yield of desired ketone8 after silica gel chromatography, along with a minor amount of unreacted ester).b²⁵

Efficient synthesis of apricoxib (1):

The product was a mixture of cis/trans R/S stereoisomers, as detected in the ¹H NMR spectrum, and was used directly in the next step without separation. Ozone was bubbled through a solution of 8 in MeOH/CH₂Cl₂ at −78°C, until all starting materials were consumed. The ozonide was then reduced to aldehyde 7 by treatment with Me₂S overnight. Removal of volatiles and subsequent addition and evaporation of toluene gave the crude 1,4-dicarbonyl compound 7 which was sufficiently pure for the following condensation step. The ¹H NMR signal at 9.78 ppm of the crude product confirmed the formation of the aldehyde. No attempt was made to characterize the enantiomeric ratio of 7 since the dehydration/aromatization reaction of the next step removes the chirality of the product. Treatment of 7 with sulfanilamide in 40% acetic acid-acetonitrile at 70°C for three hours resulted in a brown product. Purification by silica gel flash chromatography yielded 71% of pure 1 as a white solid.c²⁶

a24. Dorr AA, Lubell WD. Can J Chem. 2007;85:1006.

b25. Synthesis of 1-(4-ethoxy-phenyl)-3-methyl-hex-4-en-1-one (8): To a stirred suspension of CuCN (1.8 g, 20.0 mmol) in 50 mL of dry THF at −78°C under argon, a solution of 1-propenylmagnesium bromide (133.2 mmol, 265 mL of 0.5 M solution in THF) was added dropwise. The slurry was stirred for an additional 30 min and then a solution of methyl 4-ethoxybenzoate (6.0 g, 33.3 mmol) in 60 mL of dry THF was added slowly. The stirred reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with ice cold saturated aqueous NaH₂PO₄ (100mL) and the mixture was extracted with ether (4 × 100 mL). The combined ether extracts were washed with brine (2 × 100mL), dried (MgSO₄), filtered, and evaporated to dryness. The crude homoallylic ketone was purified by silica gel flash chromatography using a gradient of ethyl acetate in hexane as the eluent to give 8 (7.4 g, 95%) as a colorless oil. ¹H NMR (CDCl₃, 300.0 MHz) δ 1.04–1.07 (m, 3H), 1.44 (t, J = 6.9 Hz, 3H), 1.6–1.64 (m, 3H), 2.8–2.96 (m, 2.5H), 3.2 (m, 0.5H), 4.1 (q, J = 6.9 Hz, 2H), 5.25 (m, 0.5 H), 5.34–5.46 (m, 1.5H), 6.92 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H). ¹³C NMR (CDCl₃, 75.0 MHz) δ 12.9, 14.6, 17.9, 20.4, 21.0, 28.4, 33.0, 45.4, 45.5, 63.7, 114.1, 123.1, 123.4, 130.2, 130.3, 135.5, 136.0, 141.9, 162.7, 198.1. M+H Calcd: 233.1542; Found, 233.2482.

c26. Synthesis of Apricoxib (1): Homoallylic ketone (8) (5.0 g, 21.53 mmol) in 180 mL of CH₂Cl₂/MeOH (1:5) was treated with ozone bubbles at −78°C until a blue coloration persisted. The solution was purged with argon, 8.0 mL of dimethylsulphide (21.5 mmol) was added, and the reaction mixture then warmed slowly to rt overnight. The solvent was evaporated under vacuum to give 7 which was then diluted with 100 mL of 40 % acetic acid in acetonitrile, (v/v) and sulphanilamide (4.0 g, 23.2 mmol) was added. The mixture was refluxed until complete consumption of 1,4-dicarbonyl compound was detected by TLC (ca 3 h). After cooling to room temperature, the product was concentrated under vacuum and diluted with 250 mL of ethyl acetate. The organic layer then washed with saturated Na₂CO₃ solution (3 × 50 mL) followed by brine (1 × 50 mL), dried (MgSO₄), and evaporated to dryness. The crude brown material was purified by silica gel flash chromatography using a gradient of EtOAc in hexane to give apricoxib as white solid (5.5 g, 15.43 mmol, 71%).

m.p. 161–163°C (lit. 135–139°C¹⁴).

¹H NMR (CDCl₃, 300.0 MHz) δ 1.32 (t, J = 6.9 Hz, 3H), 2.1 (s, 3H), 3.92 (q, J = 6.9 Hz, 2H), 4.95 (s, 2H), 6.14 (m, 1H), 6.63 (m, 1H), 6.69 (d, J = 6.6 Hz, 2H), 6.94 (d, J = 6.6 Hz, 2H), 7.13 (d, J = 6.6 Hz, 2H), 7.74 (d, J= 6.6 Hz, 2H).

¹³C NMR (CDCl₃, 75.0 MHz) δ 11.7, 14.8, 63.4, 82.4, 113.2, 114.4, 121.0, 121.1, 124.9, 125.2, 127.4, 129.7, 133.6, 138.7, 144.2, 158.0

M+H Calcd: 357.1273; Found, 357.1252.

01

Click here to view.^{(2.1M, pdf)   DOWNLOAD TO GET NMR , 13C, COSY}

OR

Supplementary Material

¹H, ¹³C, and COSY NMR spectra of compounds 1 and 8.

...............

SYNTHESIS

synthesis

In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,Ndiisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib

Intermediate (V) can also be prepared by reaction of 1-(4- ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitroderivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).In an alternativestrategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishesN-(4-ethoxybenzylidene)-

4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α- amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib

reference for above

• Drugs of the Future 2011, 36(7): 503-509
• Kojima, S., Ooyama, J. (Daiichi Sankyo Co., Ltd.). Process for production of brominated acetophenone. WO 2008020617.
• Fujimoto, K., Takebayashi, T., Noguchi, Y., Saitou, T. (Daiichi Sankyo Co., Ltd.). Production of 4-methyl-1,2-diarylpyrrole and intermediate for synthesizing the same. JP 2000080078
• Kimura, T., Noguchi, Y., Nakao, A., Suzuki, K., Ushiyama, S., Kawara, A., Miyamoto, M. (Daiichi Sankyo Co., Ltd.). 1,2-Diphenylpyrrole derivatives,their preparation and their therapeutic uses. CA 2201812, EP 0799823, JP 1997823971, US 5908858.

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6. Estok, Thomas M.; Zaknoen, Sara L.; Mansfield, Robert K.; Lawhon, Tracy. Combination therapy for the treatment of cancer using COX-2 inhibitors and dual inhibitors of EGFR (ErbB1) and HER-2 (ErbB2). PCT Int. Appl. (2009), 87pp. CODEN: PIXXD2 WO 2009042613 A1 20090402 CAN 150:390183 AN 2009:385196

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9. Rohatagi, Shashank; Kastrissios, Helen; Sasahara, Kunihiro; Truitt, Kenneth; Moberly, James B.; Wada, Russell; Salazar, Daniel E. Pain relief model for a COX-2 inhibitor in patients with postoperative dental pain. British Journal of Clinical Pharmacology (2008), 66(1), 60-70.
10. Senzaki, Michiyo; Ishida, Saori; Yada, Ayumi; Hanai, Masaharu; Fujiwara, Kosaku; Inoue, Shin-Ichi; Kimura, Tomio; Kurakata, Shinichi. CS-706, a novel cyclooxygenase-2 selective inhibitor, prolonged the survival of tumor-bearing mice when treated alone or in combination with anti-tumor chemotherapeutic agents. International Journal of Cancer (2008), 122(6), 1384-1390. CODEN: IJCNAW ISSN:0020-7136. CAN 148:440459 AN 2008:228248

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13. Oitate, Masataka; Hirota, Takashi; Murai, Takahiro; Miura, Shin-ichi; Ikeda, Toshihiko. Covalent binding of rofecoxib, but not other cyclooxygenase-2 inhibitors, to allysine aldehyde in elastin of human aorta. Drug Metabolism and Disposition (2007), 35(10), 1846-1852. CODEN: DMDSAI ISSN:0090-9556. CAN 147:439860 AN 2007:1124386

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15. Moberly, James B.; Xu, Jianbo; Desjardins, Paul J.; Daniels, Stephen E.; Bandy, Donald P.; Lawson, Janet E.; Link, Allison J.; Truitt, Kenneth E. A randomized, double-blind, celecoxib- and placebo-controlled study of the effectiveness of CS-706 in acute postoperative dental pain. Clinical Therapeutics (2007), 29(3), 399-412.
16. Rohatagi, S.; Kastrissios, H.; Gao, Y.; Zhang, N.; Xu, J.; Moberly, J.; Wada, R.; Yoshihara, K.; Takahashi, M.; Truitt, K.; Salazar, D. Predictive population pharmacokinetic/pharmacodynamic model for a novel COX-2 inhibitor. Journal of Clinical Pharmacology (2007), 47(3), 358-370.

17. Moberly, James B.; Harris, Stuart I.; Riff, Dennis S.; Dale, James Craig; Breese, Tara; McLaughlin, Patrick; Lawson, Janet; Wan, Yaping; Xu, Jianbo; Truitt, Kenneth E. A Randomized, Double-Blind, One-Week Study Comparing Effects of a Novel COX-2 Inhibitor and Naproxen on the Gastric Mucosa. Digestive Diseases and Sciences (2007), 52(2), 442-450.

18. Oitate, Masataka; Hirota, Takashi; Koyama, Kumiko; Inoue, Shin-ichi; Kawai, Kenji; Ikeda, Toshihiko. Covalent binding of radioactivity from [14C] rofecoxib, but not [14C] celecoxib or [14C] CS-706, to the arterial elastin of rats. Drug Metabolism and Disposition (2006), 34(8), 1417-1422.

19. Kastrissios, H.; Rohatagi, S.; Moberly, J.; Truitt, K.; Gao, Y.; Wada, R.; Takahashi, M.; Kawabata, K.; Salazar, D. Development of a predictive pharmacokinetics model for a novel cyclooxygenase-2 inhibitor. Journal of Clinical Pharmacology (2006), 46(5), 537-548. CODEN: JCPCBR ISSN:0091-2700. CAN 145:327959 AN 2006:479516

20. Denis, Louis J.; Compton, Linda D. Method using camptothecin compounds, pyrimidine derivatives, and antitumor agents for treating abnormal cell growth. U.S. Pat. Appl. Publ. (2005), 32 pp. CODEN: USXXCO US 2005272755 A1 20051208 CAN 144:17160 AN 2005:1294044

21. Wajszczuk, Charles Paul; Gans, Hendrik J. Dekoning; Di Salle, Enrico; Piscitelli, Gabriella; Massimini, Giorgio; Purandare, Dinesh. Methods using exemestane, alone or with other therapeutic agents, for treating estrogen-dependent disorders. U.S. Pat. Appl. Publ. (2004), 21 pp., Cont.-in-part of WO 2002 72,106. CODEN: USXXCO US 2004082557 A1 20040429 CAN 140:368700 AN 2004:353144

22. Di Salle, Enrico; Piscitelli, Gabriella; Massimini, Giorgio; Purandare, Dinesh; Dekoning, Gans Hendrik. Combined method for treating hormone-dependent disorders with aromatase inactivator exemestane and other therapeutic agents. PCT Int. Appl. (2002), 49 pp. CODEN: PIXXD2 WO 2002072106 A2 20020919 CAN 137:226651 AN 2002:716096

23. McKearn, John P.; Gordon, Gary; Cunningham, James J.; Gately, Stephen T.; Koki, Alane T.; Masferrer, Jaime L. Method of using a cyclooxygenase-2 inhibitor and an integrin antagonist as a combination therapy in the treatment of neoplasia. PCT Int. Appl. (2000), 348 pp. CODEN: PIXXD2 WO 2000038786 A2 20000706 CAN 133:84244 AN 2000:456950

24. McKearn, John P.; Gordon, Gary; Cunningham, James J.; Gately, Stephen T.; Koki, Alane T.; Masferrer, Jaime L. Method of using a cyclooxygenase-2 inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia. PCT Int. Appl. (2000), 236 pp. CODEN: PIXXD2 WO 2000038730 A2 20000706 CAN 133:84243 AN 2000:456927

25. McKearn, John P.; Masferrer, Jaime L.; Milas, Luka. Combination therapy of radiation and a cyclooxygenase 2 (COX-2) inhibitor for the treatment of neoplasia. PCT Int. Appl. (2000), 96 pp. CODEN: PIXXD2 WO 2000038716 A1 20000706 CAN 133:84241 AN 2000:456913

26. McKearn, John P.; Gordon, Gary; Cunningham, James J.; Gately, Stephen T.; Koki, Alane T.; Masferrer, Jaime L. Method of using a cyclooxygenase-2 inhibitor and a matrix metalloproteinase inhibitor as a combination therapy in the treatment of neoplasia. PCT Int. Appl. (2000), 437 pp. CODEN: PIXXD2 WO 2000037107 A2 20000629 CAN 133:68922 AN 2000:441655

27. Noguchi, Yasuo; Saito, Toshinori; Fujimoto, Katsuhiko; Takebayashi, Toyonori. Preparation of 4-methyl-1,2-diarylpyrroles and and their intermediates. Jpn. Kokai Tokkyo Koho (2000), 14 pp. CODEN: JKXXAF JP 2000080078 A 20000321 CAN 132:207760 AN 2000:181022

28. Kurakata, Shinichi; Hanai, Masaharu; Kanai, Saori; Kimura, Tomio. Use of cyclooxygenase-2 inhibitors for the treatment and prevention of tumors, tumor-related disorders and cachexia. Eur. Pat. Appl. (1999), 49 pp. CODEN: EPXXDW EP 927555 A1 19990707 CAN 131:82985 AN 1999:440003

29. Kimura, Fumio; Noguchi, Yasuo; Nakao, Akira; Suzuki, Keisuke; Ushiyama, Shigeru; Kawahara, Akihiro; Miyamoto, Masaaki. Diphenylpyrrole derivatives as cyclooxygenase-2 inhibitors. Jpn. Kokai Tokkyo Koho (1999), 69 pp.

30. Kimura, Tomio; Noguchi, Yasuo; Nakao, Akira; Suzuki, Keisuke; Ushiyama, Shigeru; Kawara, Akihiro; Miyamoto, Masaaki. Preparation of 1,2-diphenylpyrroles as cyclooxygenase-2 inhibitors. Eur. Pat. Appl. (1997), 140 pp. CODEN: EPXXDW EP 799823 A1 19971008 CAN 127:331392 AN 1997:678926

31. Rao P N Praveen; Grover Rajesh K Apricoxib, a COX-2 inhibitor for the potential treatment of pain and cancer. IDrugs : the investigational drugs journal (2009), 12(11), 711-22.

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5  LUMIRACOXIB

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
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 namePrexige (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 ofdiclofenac (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 EventTrial) 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. Prexedewas 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 NovartisHealthcare Phils. Inc. (Novartis) to remove (recall) all lumiracoxib from local drug stores in 2 weeks due to the harmful effects of the drug (potential seriousliver-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.

External links

• Prexige
• Forbes
• FDA request more information September 23, 2003
• NPS RADAR
• FDA – Background Document for Lumiracoxib 1/13/2005
• http://www.nzherald.co.nz/category/story.cfm?c_id=278&objectid=10459030

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6 ROFECOXIB

ROFECOXIB

MK-966, MK-0966, Vioxx

162011-90-7

C17-H14-O4-S

314.3596

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 osteoarthritis, acute 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 Vioxx, Ceoxx, and Ceeoxx.

ROFECOXIB

SYSTEMATIC (IUPAC) NAME
4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one
CLINICAL DATA
PREGNANCY CAT.	C (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
IDENTIFIERS
CAS NUMBER	162011-90-7
ATC CODE	M01AH02
PUBCHEM	CID 5090
DRUGBANK	DB00533
CHEMSPIDER	4911
UNII	0QTW8Z7MCR
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

See also: Cyclooxygenase

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]

Pharmacokinetics

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

See also: Non-steroidal anti-inflammatory drug

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 accident, transient 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 polyps. Celecoxib 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 ibuprofen, diclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet aggregation properties.

Withdrawal

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 = http://www.nature.com/drugdisc/news/articles/433790b.html 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.

Litigation

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]

Synthesis

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.

Footnotes

1. Jump up^ http://www.npr.org/templates/story/story.php?storyId=4054991
2. Jump up^ “Up to 140,000 heart attacks linked to Vioxx.”. New Scientist. 2005-01-25. p. 1.
3. Jump up^ “Merck Sees Slightly Higher 2007 Earnings”. New York Times. Reuters. 2006-12-07. p. A1.
4. Jump up^ 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/NEJM200011233432103. PMID 11087881. edit
5. ^ Jump up to:a b c d Merck & Co. VIOXX (rofecoxib tablets and oral suspension). Accessed at: http://www.merck.com/product/usa/pi_circulars/v/vioxx/vioxx_pi.pdf 01 Feb 2010
6. ^ Jump up to:a b Gold Standard Inc. Rofecoxib Vioxx Accessed at: http://www.mdconsult.com/das/pharm/body/181267313-3/946823742/full/2399 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 12793839. edit
8. Jump up^ 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.2004.08.005. PMID 15501312. edit
9. ^ Jump up to:a b Scott, L. J.; Lamb, H. M. (1999). “Rofecoxib”. Drugs 58 (3): 499–505; discussion 506–7. doi:10.2165/00003495-199958030-00016. PMID 10493277. edit
10. Jump up^ Winstein, Keith J. (March 11, 2009). “Top Pain Scientist Fabricated Data in Studies, Hospital Says”. The Wall Street Journal.
11. Jump up^ 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 9597150. edit
12. Jump up^ sfgate.com
13. Jump up^ www.saferdrugsnow.org
14. Jump up^ 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.71.12.933. PMID 15641522. edit
15. Jump up^ 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.162.10.1099. PMID 12020178. edit
16. Jump up^http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166383.pdf
17. Jump up^ 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/NEJMe058314. PMID 16339408. edit
18. Jump up^ http://www.forbes.com/work/feeds/ap/2006/02/13/ap2523250.html. Missing or empty |title= (help)[dead link]
19. ^ Jump up to:a b 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 16495386. edit
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/NEJMc066096. PMID 16495387. edit
21. Jump up^ http://pipeline.corante.com/archives/2006/02/22/nejm_vs_its_contributors_round_two.php
22. Jump up^ http://dimer.tamu.edu/simplog/archive.php?blogid=3&pid=3293
23. Jump up^ http://genetics.case.edu/faculty2.php?fac=ejt9
24. Jump up^ http://www.medicinenet.com/script/main/art.asp?articlekey=56384&page=2
25. Jump up^ http://www.beasleyallen.com/news/vioxx-plaintiffs-seek-mistrial-after-allegation-on-merck-study/
26. ^ Jump up to:a b David Armstrong (2006-05-15). “How the New England Journal Missed Warning Signs on Vioxx”. Wall Street Journal. p. A1.
27. Jump up^ 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/hc4401.100078. PMID 11696466. edit
28. Jump up^ 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/NEJMoa050493. PMID 15713943. edit
29. Jump up^ http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf
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 15625749. edit
31. ^ Jump up to:a b 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.jrv60015. PMID 16968832. edit
32. Jump up^ 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/NEJMoa050405. PMID 15713944. edit
33. Jump up^ 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/NEJMoa050330. PMID 15713945. edit
34. Jump up^ “European Medicines Agency concludes action on COX-2 inhibitors” (pdf). European Medicines Agency. Retrieved 2008-04-16.
35. Jump up^ “Merck Announces Voluntary Worldwide Withdrawal of VIOXX” (pdf). Retrieved 2008-04-16.
36. Jump up^ “Congress Questions Vioxx, FDA”. PBS NewsHour. 2004-11-18. Retrieved 2013-06-03.
37. Jump up^ “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. Jump up^ Drug unfit for sale, says judge in compo case The Age, March 6, 2010
39. Jump up^ http://bioline.utsc.utoronto.ca/archive/00002693/01/dv04120.pdf#search=%22acne%20rofecoxib%22
40. Jump up^ http://vioxxlawyer.org/rofecoxib-synthesis/

References

• 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 Product, Scientific 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

• National Public Radio 2004 Q&A on the case, following withdrawal announcement
• Court TV’s full coverage of the Vioxx civil trials
• Merck website on Vioxx litigation
• FDA Public Health Advisory on Vioxx
• David Michaels. Doubt is Their Product Scientific American, June 2004, p. 96-101
• JURIST, Much Pain, Much Gain: Skeptical Ruminations on the Vioxx Litigation
• Ted Frank, American Enterprise Institute, The Vioxx Litigation, Part I and Part II, December 2005
• briandeer.com – Vioxx: the UK connection
• Campaign for compensation for Vioxx victims outside the US

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7 VALDECOXIB

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 ofosteoarthritis, 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 attackand 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. TheAmerican 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

An editor has expressed a concern that this section lends undue weight to certain ideas relative to the article as a whole. Please help to discuss and resolve the dispute before removing this message. (December 2012)

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
UNII	2919279Q3W
KEGG	D02709
CHEBI	CHEBI:63634
CHEMBL	CHEMBL865
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

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]

• FDA Alert on Bextra withdrawal
• Large systematic review of adverse renal and arrhythmia risk of valdcoxib and other COX-2 inhibitors, JAMA 2006