PIROXICAM

PIROXICAM

• Molecular FormulaC₁₅H₁₃N₃O₄S
• Average mass331.346 Da

1,1-Dioxyde de 4-hydroxy-2-méthyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide

13T4O6VMAM

252-974-3[EINECS]

2H-1,2-Benzothiazine-3-carboxamide, 4-hydroxy-2-methyl-N-2-pyridinyl-, 1,1-dioxide

36322-90-4[RN]37134

-Hydroxy-2-methyl-3-(pyrid-2-yl-carbamoyl)-2H-1,2-benzothiazine 1,1-dioxide

Piroxicam 
CAS Registry Number: 36322-90-4 
CAS Name: 4-Hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide 
Additional Names: 3,4-dihydro-2-methyl-4-oxo-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide 
Manufacturers’ Codes: CP-16171 
Trademarks: Artroxicam (Coli); Baxo (Toyama); Bruxicam (Bruschettini); Caliment (Apotex); Erazon (Krka); Feldene (Pfizer); Flogobene (Farge); Geldene (Pfizer); Improntal (Kabi); Larapam (Lagap); Pirkam (DAK); Piroflex (Lagap); Reudene (ABC); Riacen (Chiesi); Roxicam (Gramon); Roxiden (Pulitzer); Sasulen (Andreu); Solocalm (Microsules); Zunden (Luitpold)Molecular Formula: C15H13N3O4S 
Molecular Weight: 331.35 
Percent Composition: C 54.37%, H 3.95%, N 12.68%, O 19.31%, S 9.68% 
Literature References: Non-steroidal anti-inflammatory with long half-life. Prepn (keto form): J. Lombardino, DE1943265; idem,US3591584 (1970, 1971 to Pfizer).Synthesis and biological properties: J. Lombardino, E. Wiseman, J. Med. Chem.15, 848 (1972); J. Lombardino et al.,ibid.16, 493 (1973). Pharmacology: E. Wiseman et al.,Arzneim.-Forsch.26, 1300 (1976). Evaluation of ulcerogenic effects: G. Palacios et al.,Methods Find. Exp. Clin. Pharmacol.9, 353 (1987). Clinical pharmacology: L. Martinez et al.,ibid.10, 729 (1988). Review:eidem, in Pharmacological and Biochemical Properties of Drug Substancesvol. 3, M. E. Goldberg, Ed. (Am. Pharm. Assoc., Washington, DC, 1981) pp 324-346. Review of pharmacology and therapeutic efficacy: R. N. Brogden et al.,Drugs22, 165-187 (1981); eidem,ibid.28, 292-323 (1984). Symposium on clinical efficacy and safety: Am. J. Med.81, Suppl. 5B, 1-55 (1986). Comprehensive description: M. Mihalic et al.,Anal. Profiles Drug Subs.15, 509-531 (1986). 
Properties: Crystals from methanol, mp 198-200°. pKa 6.3 (2:1 dioxane-water). LD50 orally in mice: 360 mg/kg (Wiseman). 
Melting point: mp 198-200° 
pKa: pKa 6.3 (2:1 dioxane-water) 
Toxicity data: LD50 orally in mice: 360 mg/kg (Wiseman) 
Derivative Type: Cinnamic acid ester 
CAS Registry Number: 87234-24-0 
Additional Names: Piroxicam cinnamate; cinnoxicam 
Manufacturers’ Codes: SPA-S-510 
Trademarks: Sinartrol (SPA); Zelis (Proter); Zen (Prophin) 
Molecular Formula: C24H19N3O5S 
Molecular Weight: 461.49 
Percent Composition: C 62.46%, H 4.15%, N 9.11%, O 17.33%, S 6.95% 
Derivative Type: Compd with b-cyclodextrinCAS Registry Number: 121696-62-6 
Trademarks: Brexin (Chiesi); Cicladol (Master); Cycladol (Promedica) 
Molecular Formula: C57H83N3O39S 
Molecular Weight: 1466.33 
Percent Composition: C 46.69%, H 5.71%, N 2.87%, O 42.55%, S 2.19% 
Therap-Cat: Anti-inflammatory. 
Keywords: Anti-inflammatory (Nonsteroidal); Thiazinecarboxamides.

• EINECS:252-974-3
• LD₅₀:250 mg/kg (M, p.o.);
  216 mg/kg (R, p.o.);
  108 mg/kg (dog, p.o.)

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class used to relieve the symptoms of painful inflammatory conditions like arthritis.^[3][4] Piroxicam works by preventing the production of endogenous prostaglandins] which are involved in the mediation of pain, stiffness, tenderness and swelling.^[3] The medicine is available as capsules, tablets and (not in all countries) as a prescription-free gel 0.5%.^[5] It is also available in a betadex formulation, which allows a more rapid absorption of piroxicam from the digestive tract.^[3] Piroxicam is one of the few NSAIDs that can be given parenteral routes.

It was patented in 1968 by Pfizer and approved for medical use in 1979.^[6] It became generic in 1992,^[7] and is marketed worldwide under many brandnames.^[1]

Medical uses

It is used in the treatment of certain inflammatory conditions like rheumatoid and osteoarthritis, primary dysmenorrhoea, postoperative pain; and act as an analgesic, especially where there is an inflammatory component.^[3] The European Medicines Agency issued a review of its use in 2007 and recommended that its use be limited to the treatment of chronic inflammatory conditions, as it is only in these circumstances that its risk-benefit ratio proves to be favourable.^[5][8]

Adverse effects

See also: Nonsteroidal anti-inflammatory drug

As with other NSAIDs the principal side effects include: digestive complaints like nausea, discomfort, diarrhoea and bleeds or ulceration of the stomach, as well as headache, dizziness, nervousness, depression, drowsiness, insomnia, vertigo, hearing disturbances (such as tinnitus), high blood pressure, oedema, light sensitivity, skin reactions (including, albeit rarely, Stevens–Johnson syndrome and toxic epidermal necrolysis) and rarely, kidney failure, pancreatitis, liver damage, visual disturbances, pulmonary eosinophilia and alveolitis.^[5] Compared to other NSAIDs it is more prone to causing gastrointestinal disturbances and serious skin reactions.^[5]

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.^[9][10] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.^[9][10]

Mechanism of action

See also: Nonsteroidal anti-inflammatory drug

Piroxicam is an NSAID and, as such, is a non-selective COX inhibitor possessing both analgesic and antipyretic properties.^[5]

Chemical properties

Piroxicam exists as alkenol tautomer in organic solvents and as zwitterionic form in water.^[11]

History

The project that produced piroxicam began in 1962 at Pfizer; the first clinical trial results were reported in 1977, and the product launched in 1980 under the brand name “Feldene”.^[7][12] Major patents expired in 1992^[7] and the drug is marketed worldwide under many brandnames.^[1]

NMR

SYN

https://pubs.acs.org/doi/10.1021/jp1084444

Influence of Structure on the Spectroscopic Properties of the Polymorphs of Piroxicam

SYN

https://www.sciencedirect.com/science/article/abs/pii/S092420310400058X?via%3

PATENT

CN 101210013

https://patents.google.com/patent/CN101210013A/enIn the glassed steel reaction vessels of 2000L, add first ethyl ester thing 140Kg, dimethylbenzene 1500L, silica gel 10Kg.Be warming up to 100 ℃ of amino pyrrole 52Kg of adding 2-, continue to be warming up to the solvent refluxing temperature, keep refluxing slowly, steam the ethanol of reaction generation and the mixture of dimethylbenzene simultaneously, TLC follows the tracks of reaction, and reaction in 4.5-5 hour finishes.Underpressure distillation, the control temperature in the kettle is no more than 70 ℃, when the system volume be about cumulative volume 1/3 the time stop distillation, be cooled to normal temperature, stir 6-8h and filter, be i.e. crude product.Crude product adds methyl alcohol 1500L and adds the 15Kg gac, refluxes 30 minutes, filters, and is cooled to normal temperature, stirs 6-8h, methyl alcohol drip washing, 60-70 ℃ is dried by the fire 3-5h, measure product 140.5Kg, yield 85%.Press Cp2005 version standard detection, outward appearance; Off-white color, content 〉=99%.Methanol mother liquor reclaims methyl alcohol to overall 1/3 o’clock, and cooling stirring at normal temperature 6-8h filters and collects product, oven dry measure product 10Kg, yield 5.7%, this product meet the Cp2005 version and require to add up to yield.Add up to yield 90.7%.PAPER Bulletin of the Korean Chemical Society, 26(11), 1771-1775; 2005 

SYN

1. Drebushchak, V. A.; Journal of Thermal Analysis and Calorimetry 2006, V84(3), P643-649 
2.  Gehad, G. Mohamed; Vibrational Spectroscopy 2004, V36(1), P97-104 
3.  Pajula, Katja; Molecular Pharmaceutics 2010, V7(3), P795-804 
4.  Wassvik, Carola M.; European Journal of Pharmaceutical Sciences 2006, V29(3-4), P294-305
5.  Wassvik, Carola M.; Journal of Medicinal Chemistry 2008, V51(10), P3035-3039
6.  Zayed, M. A.; Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy 2004, V60A(12), P2843-2852 
7.  Zia-ur-Rehman, Muhammad; Bulletin of the Korean Chemical Society 2005, V26(11), P1771-1775 
8.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 
9.  Stulzer, H. K.; Pharmaceutical Chemistry Journal 2008, V42(4), P215-219 CAPLUS
10.  Drebushchak, V. A.; Journal of Thermal Analysis and Calorimetry 2006, V86(2), P303-309 
11.  Hughes, Laura D.; Journal of Chemical Information and Modeling 2008, V48(1), P220-232 
12.  Laban, Gunter; DD 260398 A3 1988 
13.  Svoboda, Jiri; Collection of Czechoslovak Chemical Communications 1986, V51(5), P1133-9 
14. (26) Perillo, Isabel A.; Journal of Heterocyclic Chemistry 1983, V20(1), P155-60 
15.  Zak, Bohumil; CS 276217 B6 1992 CAPLUS
16.  Dalla Croce, Piero; Journal of Chemical Research, Synopses 1986, (4), P150-1
17.  Vemavarapu, Chandra; Powder Technology 2009, V189(3), P444-453 
18.  Sanghavi, N. M.; Indian Journal of Technology 1989, V27(2), P93-5 
19.  “PhysProp” data were obtained from Syracuse Research Corporation of Syracuse, New York (US)
20. Mohamed, Gehad G.; Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy 2004, V60A(13), P3141-3154 
21.  Zayed, M. A.; Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy 2006, V64A(1), P216-232 
22.  Habibi-Yangjeh, Aziz; Bulletin of the Korean Chemical Society 2008, V29(4), P833-841 
23. Mahlin, Denny; Molecular Pharmaceutics 2011, V8(2), P498-506 
24.  Kozjek, Franc; Acta Pharmaceutica Jugoslavica 1985, V35(4), P275-81 
25.  Laban, Gunter; DD 258532 A3 1988 
26.  Caira, Mino R.; Journal of Pharmaceutical Sciences 1998, V87(12), P1608-1614 
27.  Mohamed, Gehad G.; Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy 2005, V62A(4-5), P1165-1171 
28.  Lin, Yannan; Journal of Pharmaceutical and Biomedical Analysis 2010, V51(4), P979-984 

References

1. ^ Jump up to:^a b c Drugs.com Drugs.com international listings for piroxicamPage accessed July 3, 2015
2. ^ https://www.ema.europa.eu/documents/psusa/piroxicam-list-nationally-authorised-medicinal-products-psusa/00002438/202004_en.pdf
3. ^ Jump up to:^{a b c d e f g} Brayfield, A, ed. (14 January 2014). “Piroxicam”. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 24 June 2014.
4. ^ “TGA Approved Terminology for Medicines, Section 1 – Chemical Substances” (PDF). Therapeutic Goods Administration, Department of Health and Ageing, Australian Government. July 1999: 97.
5. ^ Jump up to:^{a b c d e} Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 665, 673–674. ISBN 978-0-85711-084-8.
6. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 519. ISBN 9783527607495.
7. ^ Jump up to:^a b c Lombardino, JG; Lowe, JA 3rd (2004). “The role of the medicinal chemist in drug discovery–then and now”. Nat Rev Drug Discov. 3 (10): 853–62. doi:10.1038/nrd1523. PMID 15459676. S2CID 11225541.. See: [1] Box 1: Discovery of piroxicam (1962–1980)
8. ^ “COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) OPINION FOLLOWING AN ARTICLE 31(2) REFERRAL PIROXICAM CONTAINING MEDICINAL PRODUCTS” (PDF). European Medicines Agency. London, UK: European Medicines Agency. 20 September 2007. Retrieved 24 June 2014.
9. ^ Jump up to:^a b “FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications”. U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Retrieved 15 October 2020.  This article incorporates text from this source, which is in the public domain.
10. ^ Jump up to:^a b “NSAIDs may cause rare kidney problems in unborn babies”. U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020.  This article incorporates text from this source, which is in the public domain.
11. ^ Ivanova D, Deneva V, Nedeltcheva D, Kamounah FS, Gergov G, Hansen PE, Kawauchi S, Antonov L (2015). “Tautomeric transformations of piroxicam in solution: a combined experimental and theoretical study”. RSC Advances. 5 (40): 31852–31860. doi:10.1039/c5ra03653d.
12. ^ Weintraub M, Jacox RF, Angevine CD, Atwater EC (1977). “Piroxicam (CP 16171) in rheumatoid arthritis: a controlled clinical trial with novel assessment techniques”. Journal of Rheumatology. 4 (4): 393–404. PMID 342691.

Further reading

• Dean L (2019). “Piroxicam Therapy and CYP2C9 Genotype”. In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 30742401. Bookshelf ID: NBK537367.

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