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Lefucoxib (乐福昔布)

December 3, 2015 7:26 am / Leave a comment

Lefucoxib (乐福昔布)

5-(3,4-dimethyl-phenyl)-1-methanesulfonyl-3-trifluoromethol-pyrazole

1 [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole

CAS 849048-84-6

Molecular Formula:	C₁₉H₁₇F₃N₂O₂S
Molecular Weight:	394.41069 g/mol

IND FILED

Prostaglandin G/H Synthase 2 (PTGS2; COX-2) Inhibitors

A COX-2 inhibitor potentially for the treatment of rheumatoid arthritis.

cyclooxygenase-2 (COX-2) inhibitor

National Center of Biomedical Analysis

冉允章, 梅世昌

梅世昌, 冉允章

CHINA FLAG

PATENT

CN 1468854

http://www.google.com/patents/CN1468854A?cl=en

Example 1

1 [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole (I1)

1- (3,4- two toluene-yl) -4,4,4-trifluoro-methyl – D-1,3-dione (IV1) of sodium metal was weighed 2.3g (0.1mol) was added 50ml of anhydrous toluene to prepare a sodium sand. After cooling, ethanol was added dropwise 12ml, and then heated at 60 ℃, complete reaction of sodium metal. After cooling to room temperature, was added 3,4-dimethylphenyl ethanone 23.8g (0.1mol) and trifluoroacetic ethyl acetate 20ml (0.2mol), reacted at 100 ℃ 5 hours. Toluene was distilled off under reduced pressure, a 10% aqueous hydrochloric acid was added, the pH was adjusted to 2-3, extracted with ethyl acetate, washed with water, dried over anhydrous MgSO4, ethyl acetate was distilled off under reduced pressure. Then under reduced pressure, distillation, collecting fractions 105-107 ℃ / 0.7mmHg, was 14.6g, 60% yield.

1- [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole (I1) take the above-prepared substituted (IV1) 2.38g (0.01mol ), 15ml of ethanol, then added p-methanesulfonyl phenyl hydrazine salt alkoxide 2.3g (0.01ml). Was refluxed for 15 hours. Place the refrigerator overnight, the crystals were collected by filtration, recrystallized from ethanol, mp 129-31 ℃, to give 3.1 g.

Elemental analysis: C19H17F3N2O2S Calculated: C, 57.86; H, 4.34; N, 7.10 Found: C, 57.97; H, 4.29; N, 7.20MS (m / z): 395 (M + 1)

References

Cheng, Feixiong, Edited by Lee, Philip W, From Handbook of Metabolic Pathways of Xenobiotics (2014), 4, 1655-1656

Bi, X.; Meng, Z.; Chen, H.; Zhu, X.; Dou, G.
In vivo and in vitro metabolism of lefucoxib in rats, J Pharm Biomed Anal. 2008 Sep 10;48(1):134-9. doi: 10.1016/j.jpba.2008.04.024. Epub 2008 Apr 30.

Bi, X.; Meng, Z.; Dou, G. Determination of lefucoxib in rat plasma, urine, and feces by high-performance liquid chromatography with fluorescence detection: Application in pharmacokinetic studies
J Chromatogr B Anal Technol Biomed Life Sci 2007, 850(1-2): 199

Talanta (2011), 85(1), 8-27

Jiefangjun Yaoxue Xuebao (2009), 25(6), 496-498.

Yaowu Fenxi Zazhi (2006), 26(9), 1222-1224.

Zhongguo Yaolixue Yu Dulixue Zazhi (2007), 21(2), 147-151.

CN101497585B	Jan 31, 2008	Jan 12, 2011	中国科学院理化技术研究所	Method for photocatalytic synthesis of 1,3,5-trisubstituted-2-pyrazole derivative

China PLA General Hospital

//////////c1c(ccc(c1C)C)c2n(nc(c2)C(F)(F)F)c3ccc(cc3)S(=O)(=O)C

CC1=C(C=C(C=C1)C2=CC(=NN2C3=CC=C(C=C3)S(=O)(=O)C)C(F)(F)F)C

NS 398 is a COX-2 inhibitor used in the study of the function of cyclooxygenases.

August 3, 2014 8:47 am / 1 Comment on NS 398 is a COX-2 inhibitor used in the study of the function of cyclooxygenases.

NS 398

N-[2-(Cyclohexyloxy)-4-nitrophenyl]methanesulfonamide

Taisho (Originator)

Taisho Pharmaceutical Co. Ltd

N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.

123653-11-2, 123653-43-0 (Ca salt), 123653-44-1 (Na salt)

Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Cyclooxygenase-2 Inhibitors

NS-398 is a COX-2 inhibitor used in the study of the function of cyclooxygenases.^[2]

Selective cyclooxygenase-2 inhibitor (IC₅₀ values are 3.8 and > 100 μM for COX-2 and COX-1 respectively). Orally active. Anti-inflammatory, anti-pyretic, analgesic and non-ulcerogenic in vivo. Induces apoptosis and cell cycle arrest

Cyclooxygenase (COX-2) has been recently suggested to play a role in hepatocarcinogenesis. However, the exact pathway by which COX-2 affects the growth of hepatocellular carcinoma (HCC) is not clear. This study investigated the effects of a specific COX-2 inhibitor, NS-398, on the cell proliferation and apoptosis of COX-2-expressing and non-expressing HCC cell lines.

In addition, the modulatory effect of NS-398 on apoptosis-regulating gene expression was examined. Semi-quantitative/quantitative reverse transcription-polymerase chain reaction and Western blot showed that Hep3B and HKCI-4 cells expressed COX-2 mRNA and protein, but HepG2 cells did not. NS-398 suppressed cell proliferation and induced apoptosis in the two COX-2-expressing cell lines in a dose-dependent manner, but not in HepG2 cells.

Fas ligand mRNA and protein expression were increased by the treatment with NS-398 (10 micro M) in COX-2-expressing cell lines. The expressions of Fas and Bcl-2 family genes (Bax, Bcl-2, Bcl-xL, Bcl-xS) were not affected by NS-398 treatment in all three cell lines. In conclusion, specific COX-2 inhibitor suppresses cell proliferation and induces apoptosis in HCC cell lines that express COX-2. Our finding suggests that COX-2 inhibition may offer a new approach for HCC chemoprevention.

Identifiers
IUPAC name N-[2-(Cyclohexyloxy)-4-nitrophenyl]methanesulfonamide
CAS number	123653-11-2
PubChem	4553

Jmol-3D images	Image 1
SMILES [show]
Properties
Molecular formula	C₁₃H₁₈N₂O₅S
Molar mass	314.36 g mol⁻¹
Appearance	Off-white solid
Solubility in water	Insoluble
Solubility in DMSO	5 mg/mL
Hazards
S-phrases	S22 S24/25

The condensation of 2-fluoronitrobenzene (I) with cyclohexanol (II) by means of NaH gives 2-(cyclohexyloxy)nitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 2-(cyclohexyloxy)aniline (IV). The acylation of (IV) with methanesulfonyl chloride (V) in pyridine affords N-(2-cyclohexyloxy phenyl)methanesulfonamide (VI), which is finally nitrated with concentrated HNO3 in hot acetic acid.

EP 0317332

http://www.google.com/patents/EP0317332A2?cl=en

[0045]

(1) To 40 ml of a dioxane suspension containing 0.92 g of 60% sodium hydride was added 2.5 ml of cyclohexanol at room temperature over a 15-minute period, and the mixture was stirred at the same temperature for 1 hour and then at 50°C for 3.5 hours. The temperature of the reaction solution was returned to room temperature, 10 ml of a dioxane containing 3.2 g of 2-fluoronitrobenzene was added dropwise, and the mixture was stirred at room temperature overnight. The dioxane was evaporated, the residue was extracted with chloroform, and the chloroform layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated to give an oil, which was then distilled under reduced pressure to give 3.8 g of 2-cyclohexyloxynitrobenzene.
b.p. 130 – 134°C/0.5 – 0.7 mmHg
[0046]

(2) Fifty ml of a methanol solution containing 3.7 g of 2-cyclohexyloxynitrobenzene and 0.2 g of 5% palladium on carbon was stirred at room temperature under a hydrogen atmosphere for catalytic reduction. The catalyst was removed by filtration, and the filtrate was evaporated off to give 2.9 g of 2-cyclohexyloxyaniline as pale brown crystals.
m.p. 55 – 56°C
[0047]

(3) To 20 ml of a pyridine solution containing 2.7 g of 2-cyclohexyloxyaniline was added dropwise 1.8 g of methanesulfonyl chloride under ice cooling with stirring. After completion of the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and made acidic with dilute hydrochloric acid. The crystals which formed were collected by filtration, washed with water and dried to give 3.8 g of the crude crystals, which were then recrystallized from ethanol-n hexane to give 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide.
m.p. 113 – 115°C
[0048]

(4) To 20 ml of an acetic acid solution containing 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide was added dropwise 1.5 g of 61% nitric acid on heating at 110°C over a 30-minute period, and then the mixture was stirred for 1 hour. The reaction solution was poured into ice water and neutralized with a dilute aqueous sodium hydroxide solution. The crystals which formed were collected by filtration, washed with water and dried to give 4.5 g of the crude crystals, which were then recrystallized from ethanol-n-hexane to give 3.3 g of N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.
m.p. 136 – 137°C

EP0093591A1 *	Apr 29, 1983	Nov 9, 1983	Eli Lilly And Company	Selective sulfonation process
FR2244473A1 *				Title not available
US3725451 *	Apr 13, 1970	Apr 3, 1973	Riker Laboratories Inc	Substituted benzoylhaloalkanesulfonanilides
US3840597 *	Jul 3, 1972	Oct 8, 1974	Riker Laboratories Inc	Substituted 2-phenoxy alkane-sulfonanilides
US3856859 *	Jun 8, 1973	Dec 24, 1974	Riker Laboratories Inc	Selective nitration process

Citing Patent	Filing date	Publication date	Applicant	Title
EP1535614A2 *	Aug 22, 1997	Jun 1, 2005	University OofFlorida	Materials and methods for detection and treatment of immune system dysfunctions

……………………………………………………..

The cortical collecting duct (CCD) is a major site of intrarenal prostaglandin E₂ (PGE₂) synthesis. This study examines the expression and regulation of the prostaglandin synthesizing enzymes cyclooxygenase-1 (COX-1) and -2 in the CCD. By indirect immunofluorescence using isoform-specific antibodies, COX-1 and -2 immunoreactivity was localized to all cell types of the murine M-1 CCD cell line. By immunohistochemistry, both COX-1 and COX-2 were localized to intercalated cells of the CCD on paraffin-embedded mouse kidney sections. When COX enzyme activity was measured in the M-1 cells, both indomethacin (COX-1 and -2 inhibitor) and the specific COX-2 inhibitor NS-398 effectively blocked PGE₂ synthesis. These results demonstrate that COX-2 is the major contributor to the pool of PGE₂synthesized by the CCD. By Western blot analysis, COX-2 expression was significantly upregulated by incubation with either indomethacin or NS-398. These drugs did not affect COX-1 protein expression. Evaluation of COX-2 mRNA expression by Northern blot analysis after NS-398 treatment demonstrated that the COX-2 protein upregulation occurred independently of any change in COX-2 mRNA expression. These studies have for the first time localized COX-2 to the CCD and provided evidence that the intercalated cells of the CCD express both COX-1 and COX-2. The results also demonstrate that constitutively expressed COX-2 is the major COX isoform contributing to PGE₂synthesis by the M-1 CCD cell line. Inhibition of COX-2 activity in the M-1 cell line results in an upregulation of COX-2 protein expression.

http://jasn.asnjournals.org/content/10/11/2261.abstract
…………………………………………….

NS398 inhibits the growth of OSCC cells by mechanisms that are dependent and independent of suppression of PGE₂ synthesis. Molecular targeting of COX-2, PGE₂ synthase, or PGE₂ receptors may be useful as a chemopreventive or therapeutic strategy for oral cancer.

http://clincancerres.aacrjournals.org/content/9/5/1885.full

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References

NS-398 at Sigma-Aldrich
Wei Shen, Yong Li, Ying Tang, James Cummins and Johnny Huard (2005). “NS-398, a Cyclooxygenase-2-Specific Inhibitor, Delays Skeletal Muscle Healing by Decreasing Regeneration and Promoting Fibrosis”. American Journal of Pathology 167 (4): 1105–1117.doi:10.1016/S0002-9440(10)61199-6. PMC 1603662. PMID 16192645.
MORE References

Futaki et al (1993) NS-398, a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions. Gen.Pharmacol. 24 105. PMID: 8482483.

Futaki et al (1994) NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro. Prostaglandins 47 55. PMID: 8140262.

Elder et al (2002) The MEK/ERK pathway mediates COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells. Int.J.Cancer 99 323. PMID: 11992399.

Apricoxib, A COX-2 inhibitor.

July 29, 2014 3:52 am / 1 Comment on Apricoxib, A COX-2 inhibitor.

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.

Chemical structure for apricoxib

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.

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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

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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}

Supplementary Material

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

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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.

References

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2. Zaknoen, Sara L.; Lawhon, Tracy. Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders. PCT Int. Appl. (2009), 119 pp. CODEN: PIXXD2 WO 2009070546 A1 20090604 CAN 151:24882 AN 2009:676598

3. Zaknoen, Sara L.; Lawhon, Tracy. Cancer treatment using a 1,2-diphenylpyrrole derivative cyclooxygenase 2 (COX-2) inhibitor and antimetabolite combinations. PCT Int. Appl. (2009), 107pp. CODEN: PIXXD2 WO 2009070547 A1 20090604 CAN 151:24877 AN 2009:672256

4. Estok, Thomas M.; Zaknoen, Sara L.; Mansfield, Robert K.; Lawhon, Tracy. Therapies for treating cancer using combinations of COX-2 inhibitors and anti-HER2(ErbB2) antibodies or combinations of COX-2 inhibitors and HER2(ErbB2) receptor tyrosine kinase inhibitors. PCT Int. Appl. (2009), 121pp. CODEN: PIXXD2 WO 2009042618 A1 20090402 CAN 150:390188 AN 2009:386123

5. Estok, Thomas M.; Zaknoen, Sara L.; Mansfield, Robert K.; Lawhon, Tracy. Therapies for treating cancer using combinations of COX-2 inhibitors and aromatase inhibitors or combinations of COX-2 inhibitors and estrogen receptor antagonists. PCT Int. Appl. (2009), 88pp. CODEN: PIXXD2 WO 2009042612 A1 20090402 CAN 150:390184 AN 2009:385226

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

7. Lawhon, Tracy; Zaknoen, Sara; Estok, Thomas; Green, Mark. Patient selection and therapeutic methods using markers of prostaglandin metabolism. PCT Int. Appl. (2009), 121pp. CODEN: PIXXD2 WO 2009009776 A2 20090115 CAN 150:136599 AN 2009:55595

8. Estok, Thomas M.; Zaknoen, Sara L.; Mansfield, Robert K.; Lawhon, Tracy. Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders using combination of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor. PCT Int. Appl. (2009), 104 pp. CODEN: PIXXD2 WO 2009009778 A1 20090115 CAN 150:136628 AN 2009:54177

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