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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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New Antiarthritic Drug Candidate S-2474




Shionogi Research Laboratories

cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO)

mp 135−137 °C.

S-2474,158089-95-3, 158089-96-4 ((Z)-isomer),C20-H31-N-O3-S,

E)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethylisothiazolidine 1,1-dioxide

  • Phenol, 2,6-bis(1,1-dimethylethyl)-4-[(2-ethyl-5-isothiazolidinylidene)methyl]-, S,S-dioxide, (E)-
  • 2,6-Bis(1,1-dimethylethyl)-4-[(E)-(2-ethyl-1,1-dioxido-5-isothiazolidinylidene)methyl]phenol
  • Phenol, 2,6-bis(1,1-dimethylethyl)-4-[(2-ethyl-1,1-dioxido-5-isothiazolidinylidene)methyl]-, (E)-

(E)-(5)-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474, ), which was discovered at Shionogi Research Laboratories, shows potent inhibitory effects on both cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) and is anticipated to be promising as an antiarthritic drug

synthesis of novel γ-sultam derivatives containing the di-tert-butylphenol antioxidant moiety. Several compounds with lower alkyl groups at the 2-position of the γ-sultam skeleton showed potent inhibitory activities against PGE2 production via the COX pathway and LTB4 production via the 5-LO pathway, as well as production of IL-1 in in vitro assays. Extensive pharmacological characterizations revealed that 2-ethyl-γ-sultam derivative 10b displays multiple inhibition of COX, 5-LO, and IL-1 production similar to tenidap and also good selective COX-2 inhibition like NS-398 and celecoxib. It exerted excellent antiinflammatory activity without any ulcerogenic effects and was designated as S-2474 an agent having both NSAID and cytokine modulating properties. S-2474 is now being developed as a promising alternative antiarthritic drug candidate


17th Symp Med Chem (Nov 19 1997 , Tsukuba), EP 0595546; JP 1994211819; US 5418230

The intermediate gamma-sultam (III) was prepared by condensation of 3-chloropropylsulfonyl chloride (I) with ethylamine, followed by cyclization of the resulting chloro sulfonamide (II) under basic conditions. Condensation of 3,5-di- tert-butyl-4- (methoxymethoxy) benzaldehyde (IV) with sultam (III) in the presence of LDA produced the aldol addition compound (V). Then, acid-promoted dehydration and simultaneous methoxymethyl group deprotection gave rise to a mixture of the desired E-benzylidene sultam and the corresponding Z-isomer (VII), which were separated by column chromatography.


Novel Antiarthritic Agents with 1,2-Isothiazolidine-1,1-dioxide (γ-Sultam) Skeleton: Cytokine Suppressive Dual Inhibitors of Cyclooxygenase-2 and 5-Lipoxygenase

Shionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, Japan, and Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki 216-8512, Japan
J. Med. Chem., 2000, 43 (10), pp 2040–2048
DOI: 10.1021/jm9906015
Abstract Image

Various 1,2-isothiazolidine-1,1-dioxide (γ-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the γ-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure−activity relationships (SAR) examined and some pharmacological evaluations are described.


Highly E-Selective and Effective Synthesis of Antiarthritic Drug Candidate S-2474 Using Quinone Methide Derivatives

Shionogi Research Laboratories, Shionogi & Company, Ltd., Fukushima-ku, Osaka 553-0002, Japan
J. Org. Chem., 2002, 67 (1), pp 125–128
DOI: 10.1021/jo0106795
 Abstract Image
We have developed an efficient and E-selective synthesis of an antiarthritic drug candidate (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474), in which α-methoxy-p-quinone methide is used as a key intermediate. α-Methoxy-p-quinone methide was revealed to be an equiv. to a p-hydroxy protected benzaldehyde. It reacts smoothly with α-sulfonyl carbanion to give 1,6-addn. intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.
An improved synthesis has been reported. Acid -catalyzed ketalization of aldehyde (VIII) with trimethyl orthoformate provided the dimethyl acetal (IX) which, upon thermal decomposition in refluxing xylene, gave rise to the alpha-methoxy methylenequinone derivative (X ). This was then condensed with the lithio derivative of sultam (III) to form selectively the desired E-adduct. in an analogous procedure, aldehyde (VIII) was converted to the chloromethylene compound (XI) with methanesulfonyl chloride and triethylamine in refluxing CH2Cl2 . Condensation of (XI) with the lithiated sultam (III) furnished the desired E-benzylidene sultam.


Development of One-Pot Synthesis of New Antiarthritic Drug Candidate S-2474 with High E-Selectivity

Chemical Development Department, CMC Development Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan, and Shionogi Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan
Org. Process Res. Dev., 2008, 12 (3), pp 442–446
DOI: 10.1021/op800008w

* To whom correspondence should be addressed. Telephone: +81-6-6401-8198 . Fax: +81-6-6401-1371., †

Chemical Development Department, CMC Development Laboratories.

, ‡Shionogi Research Laboratories.

Abstract Image

A one-pot synthesis of S-2474 was developed to overcome the problems of a large number of steps, low stereoselectivity, low yield, a large amount of waste, and severe reaction conditions. Aldol-type condensation of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and N-ethyl-γ-sultam was carried out with LDA and then quenched with water. Dehydration proceeded under basic conditions, providing S-2474 directly as a single isomer on the benzylidene double bond. The reaction mechanism appears to involve a quinone methide intermediate. Environmental assessment of the development of this compound is also discussed in this paper.



///////New,  Antiarthritic , Drug Candidate,  S-2474, Shionogi Research Laboratories, cyclooxygenase-2,  (COX-2),  5-lipoxygenase , (5-LO), PHASE 2, 158089-95-3, 158089-96-4, S2474, S 2474


Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors


COMPD HAS  cas no 1616882-93-9

MF……….C18 H11 F3 N2 O2
[1]​Benzopyrano[4,​3-​c]​pyrazol-​4(1H)​-​one, 3-​methyl-​1-​[4-​(trifluoromethyl)​phenyl]​-



Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors

DOI: 10.1016/j.bmcl.2014.08.050

Jagdeep Grover, Vivek Kumar, M. Elizabeth Sobhia, Sanjay M. Jachak


As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3ad, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50’s in 1.79–4.35 μM range; COX-2 selectivity index (SI) = 6.8–16.7 range). Compound 3b emerged as most potent (COX-2 IC50 = 1.79 μM; COX-1 IC50 >30 μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5 h) in comparison to celecoxib (51.44% inhibition of edema at 5 h) in carrageenan-induced rat paw edema assay. Structure–activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1.


  • a Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar (Mohali) 160062, Punjab, India
  • b Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar 160062, Punjab, India

Sanjay Corresponding author. Tel.: +91 172 2214683; fax: +91 172 2214692.


Cyclooxygenase (COX) or prostaglandin endoperoxide synthase (PGHS), catalyzes the conversion of arachidonic acid to inflammatory mediators such as prostaglandins (PGs), prostacyclins and thromboxanes. COX exists in mainly two isoforms: COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs), widely used for relief of fever, pain and inflammation, act by inhibiting COX catalyzed biosynthesis of inflammatory mediators.

However, the therapeutic use of classical NSAIDs is associated with well-known side effects at the gastrointestinal level (mucosal damage, bleeding) and, less frequently, at the renal level.

Two decades after the discovery of COX isoforms, it was recognized that selective inhibition of COX-2 might be endowed with improved anti-inflammatory properties and reduced gastrointestinal toxicity profiles than classical NSAIDs.

Overall, these selective COX-2 inhibitors (coxibs) have fulfilled the hope of possessing reduced risk in gastrointestinal events, but unfortunately cardiovascular concerns regarding the use of these agents have emerged that led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market in 2004 and 2005, respectively.

Ongoing safety concerns pertaining to the use of non-selective NSAIDs have spurred development of coxibs with improved safety profile.


cas no 1616882-93-9

mf……….C18 H11 F3 N2 O2
[1]​Benzopyrano[4,​3-​c]​pyrazol-​4(1H)​-​one, 3-​methyl-​1-​[4-​(trifluoromethyl)​phenyl]​-


Full-size image (21 K)

Scheme 1.

Reagent and conditions: (a) Piperidine, rt, 20 min; (b) ArNHNH2, EtOH, reflux, 5 h; (c) K2CO3, acetone, reflux, 24 h.


3b R1=H R2= H 4-CF3-C6H4 90
3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one (3b):
White solid; yield 90%; mp: 224–225 °C;
1H NMR (CDCl3, 400 MHz): δ ppm 7.89 (d, 2H, J = 8.32 Hz, Ar-H), 7.73 (d, 2H, J = 8.24 Hz, Ar-H), 7.45–7.52 (m, 2H, H-6, H-7), 7.16 (dd, 1H, J = 1.4, 8.2 Hz, H-9), 7.10 (td, 1H, J = 1.56, 7.38 Hz, H-8), 2.69 (s, 3H, CH3);
13C NMR (CDCl3, 100 MHz): δ ppm 157.7, 153.3, 151.5, 142.3, 141.8, 131.9, 127.2, 127.1, 127.0, 124.0, 122.2, 118.3, 111.5, 107.1, 12.8;
HRMS (ESI) m/z: Calcd for C18H11F3N2O2Na [M + Na]+ 367.0670; found 367.0676.

Synthetic Communications (2014), 44(13), 1914-1923


Jagdeep Grovera, Somendu Kumar Roya & Sanjay Madhukar Jachaka*

pages 1914-1923


Unprecedented cyclization was observed during N-sulfonylation of 3-[1-(phenylhydrazono)-ethyl]-chromen-2-one in pyridine, affording 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones. To avoid use of noxious pyridine, reaction was tried in different basic conditions and the best results were obtained with potassium carbonate in acetone. A wide range of substrates bearing either electron-donating or electron-withdrawing substituents on phenylhydrazine ring were compatible with the developed methodology. Rapid access of starting material, 3-acetylcoumarin, excellent yields of products, and use of environmentally benign base and solvent for the cyclization make this strategy an efficient and convenient method for synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones.


Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one (4b):
yield 90%; mp: 224–225 °C;
1H NMR (CDCl3, 400 MHz):δppm 2.69 (s, 3H, CH3),
7.10(td, 1H,J= 1.56, 7.38 Hz, H-8),
7.16 (dd, 1H,J= 1.4, 8.2 Hz, H-9),
7.45–7.52 (m, 2H, H-6, H-7),
7.73 (d, 2H,J= 8.24 Hz, Ar-H),
7.89 (d, 2H,J= 8.32 Hz, Ar-H);
13C NMR (CDCl3, 100MHz):
δppm 12.8, 107.1, 111.5, 118.3, 122.2, 124.0,
127.0, 127.1, 127.2, 131.9, 141.8, 142.3,
151.5, 153.3, 157.7;
HRMS (ESI)m/z: Calcd for C18H11F3N2O2Na [M + Na]+367.0670; found367.0676.





1. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727.
2. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J. B.; Meyer, E. F.; Brice, M. D.; Rodgers, J. R.; Kennard, O.; Shimanouchi, T.; Tasumi, M. J. Mol. Biol. 1977, 112, 535.

Apricoxib, A COX-2 inhibitor.


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 .


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


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

Scheme 3
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Object name is nihms324531f3.jpg
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.



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.






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.



1. Bierbach, Ulrich. Platinum acridine anti-cancer compounds and methods thereof. PCT Int. Appl. (2010), 54pp. CODEN: PIXXD2 WO 2010048499 A1 20100429 CAN 152:517954 AN 2010:529827

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

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

11. Kojima, Shunshi; Ooyama, Jo. Process for production of brominated acetophenone as drug intermediate. PCT Int. Appl. (2008), 37pp. CODEN: PIXXD2 WO 2008020617 A1 20080221 CAN 148:262335 AN 2008:220659

12. Ushiyama, Shigeru; Yamada, Tomoko; Murakami, Yukiko; Kumakura, Sei-ichiro; Inoue, Shin-ichi; Suzuki, Keisuke; Nakao, Akira; Kawara, Akihiro; Kimura, Tomio. Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects. European Journal of Pharmacology (2008), 578(1), 76-86.

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

14. Kiguchi, Kaoru; Ruffino, Lynnsie; Kawamoto, Toru; Franco, Eugenia; Kurakata, Shin-ichi; Fujiwara, Kosaku; Hanai, Masaharu; Rumi, Mohammad; DiGiovanni, John. Therapeutic effect of CS-706, a specific cyclooxygenase-2 inhibitor, on gallbladder carcinoma in BK5.ErbB-2 mice. Molecular Cancer Therapeutics (2007), 6(6), 1709-1717.

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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1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses
Use of MEK inhibitors in treating abnormal cell growth
Therapeutic combinations comprising poly (ADP-ribose) polymerases inhibitor
Method for treating abnormal cell growth
Method of using a cyclooxygenase-2 inhibitor and sex steroids as a combination therapy for the treatment and prevention of dismenorrhea
Methods and compositions for treatment and prevention of tumors, tumor-related disorders and cachexia
Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
Methods for treating estrogen-dependent disorders
Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
Method of using cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
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Methods and Compositions for the Treatment of Cancer, Tumors, and Tumor-Related Disorders
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Methods and compositions for the treatment and prevention of tumors, tumor-related disorders and cachexia
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1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses
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