HuagongsheHuagongshe Chemistry Print Report · For research reference only
Valdecoxib
BEXTRA · Valz · Valus · CS-592 · SC 65872 · Valecoxib · VALDECOXIB · AKOS 92130
Identifiers & Physical Properties
| CAS No. | 181695-72-7 |
|---|---|
| Molecular formula | C16H14N2O3S |
| Average molar mass | 314.4 g/mol |
| Monoisotopic mass | 314.07251331 g/mol |
| SMILES | Cc1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1 |
| InChIKey | LNPDTQAFDNKSHK-UHFFFAOYSA-N |
| PubChem CID | 119607 |
| ChEMBL | CHEMBL865 |
| ChEBI | CHEBI:63634 |
| EC No. | 448-010-8 |
| DTXSID | DTXSID6044226 |
Chemical & Physical Properties
| XLogP | 2.6 |
|---|---|
| Topological polar surface area | 94.6 |
| Hydrogen bond donors | 1 |
| Hydrogen bond acceptors | 5 |
| Rotatable bonds | 3 |
| Heavy atoms | 22 |
| Formal charge | 0 |
| Complexity | 462 |
| Drugs | PharmaceuticalsPharmaceuticals -> Listed in ZINC15 |
| LogP (partition coefficient) | log Kow = 2.67 /Estimated/ |
| Color/Form | White crystalline powder |
| Solubility | Soluble in methanol and ethanolfreely soluble in organic solvents and alkaline (pH=12) aqueous solutionRelatively insoluble in water (10 ug/mL) at 25 °C and pH 7>47.2 [ug/mL] (The mean of the results at pH 7.4)DMSO: >25mg/mL |
| Human Drugs | Breast FeedingLactationMilk, HumanAnalgesic AgentsAnti-inflammatory Agents, NonsteroidalFDA approved drugs -> Active ingredientPharmaceuticals |
| Melting point | 160 - 162 °C162-164°C |
| Vapor pressure | 4.6X10-10 mm Hg at 25 °C /Estimated/ |
| Henry's law constant | Henry's Law constant = 2.2X10-11 atm-cu m/mol at 25 °C /Estimated/4.5×105 mol/(m3Pa) at 25℃, HSDB (2015) |
| Physical Description | Solid |
| Other Experimental Properties | Hydroxyl radical reaction rate constant = 1.3X10-11 cu cm/molec-sec at 25 °C /Estimated/ |
| Boiling point | 481.2±55.0 °C(Predicted) |
| Density | 1.303±0.06 g/cm3(Predicted) |
| Storage conditions | room temp |
| pKa (acidity coefficient) | 9.83±0.10(Predicted) |
| Physical state | powder |
| Color | white to off-white |
| InChI | InChI=1S/C16H14N2O3S/c1-11-15(12-7-9-14(10-8-12)22(17,19)20)16(18-21-11)13-5-3-2-4-6-13/h2-10H,1H3,(H2,17,19,20) |
| InChIKey | LNPDTQAFDNKSHK-UHFFFAOYSA-N |
| SMILES | C1(S(N)(=O)=O)=CC=C(C2=C(C)ON=C2C2=CC=CC=C2)C=C1 |
| CAS DataBase Reference | 181695-72-7(CAS DataBase Reference) |
| EWG's Food Scores | 1 |
| NCI Dictionary of Cancer Terms | valdecoxib |
| FDA UNII | 2919279Q3W |
| NCI Drug Dictionary | Bextra |
| ATC code | M01AH03 |
| UNSPSC Code | 12352200 |
| NACRES | NA.77 |
| GHS pictogram | GHS08,GHS09 |
| Signal word | Warning |
| GHS hazard statements | H361d-H373-H410 |
| GHS precautionary statements | P201-P202-P260-P273-P280-P308+P313 |
| Hazard symbols | Xn,N |
| Risk statements (R) | 63-48/22-51/53 |
| Safety statements (S) | 36/37-61 |
| UN transport number | UN 3077 9 / PGIII |
| Water hazard class (WGK) | 3 |
| Storage class | 11 - Combustible Solids |
| Hazard class | Aquatic Chronic 1Repr. 2STOT RE 2 |
| Hazardous substances data | 181695-72-7(Hazardous Substances Data) |
Safety & Regulations
| GHS classification | WarningH361 (97.4%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]P203, P260, P273, P280, P318, P319, P391, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 39 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity] |
|---|---|
| Regulatory information | Status: Active Update: 20-08-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/17744 |
| FDA requirements | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl valdecoxib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Special Reports | Chavez ML, DeKorte CJValdecoxib: A ReviewClin Ther 25 (3): 817-51(2003) |
| Hazard Classes and Categories | Repr. 2 (100%)Repr. 2 (97.4%) |
| Disposal methods | SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air qualitypotential migration in soil or watereffects on animal, aquatic, and plant lifeand conformance with environmental and public health regulations. |
| Interactions | Valdecoxib produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alonetherefore, monitoring of lithium concentrations for signs of lithium toxicity is recommended during concurrent usehowever, lithium has no effect on valdecoxib pharmacokinetics.In clinical trials, concurrent use administration of valdecoxib 20 mg with multiple dose of ketoconazole and fluconazole produced increased plasma exposure of valdecoxib by 62% when coadministered with fluconazole and 38% when coadministered with ketoconazole, the increase in plasma concentration of valdecoxib was due to the inhibition of valdecoxib metabolism via p450 2C9 and 3A4 by fluconazole and ketoconazole.Single and multiple dose crossover studies of valdecoxib 40 mg twice daily for seven days with warfarin 1 to 8 mg daily were associated with significant increases in plasma exposures of warfarin and an increase in prothrombin time (measured as INR)while mean INR values were only slightly increased, the day-to-day variability in individual INR values increasedmonitoring of INR is recommended for the first few weeks after valdecoxib is initiated or the dose is changed.Concurrent use /of angiotensin-converting enzyme (ACE) inhibitors/ with valdecoxib may decrease the antihypertensive effects of ACE inhibitorsalso, risk of renal failure is increased in patients taking these medications.For more Interactions (Complete) data for VALDECOXIB (14 total), please visit the HSDB record page. |
| Environmental fate | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 190,000(SRC), determined from a structure estimation method(2), indicates that valdecoxib is expected to be immobile in soil(SRC). Volatilization of valdecoxib from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.2X10-11 atm-cu m/mole(SRC), determined using a fragment constant estimation method(3). Valdecoxib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-10 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 190,000(SRC), determined from a structure estimation method(2), indicates that valdecoxib is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.2X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 23(SRC), from an estimated log Kow of 2.67(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data were not available(SRC, 2005).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), valdecoxib, which has an estimated vapor pressure of 4.6X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase valdecoxib may be removed from the air by wet and dry deposition(SRC). |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc for valdecoxib can be estimated to be 190,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that valdecoxib is expected to be immobile in soil. |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Symptoms of overdose may include lethargy, drowsiness, nausea, vomiting, and epigastric pain. These are usually reversible with supportive treatment. GI bleeding, hypertension, acute renal failure, respiratory depression, and coma may occur.Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose./SIGNS AND SYMPTOMS/ Serious, potentially life-threatening skin reactions, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (TEN), have been reported during postmarketing surveillance of valdecoxib. Fatalities due to Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported. While serious reactions may occur at any time during therapy with valdecoxib, the risk of such reactions appears to be highest within the first 2 weeks of therapy. While patients with a history of sulfonamide hypersensitivity may be at greater risk for skin reactions, patients without such a history also are at risk for serious skin reactions. These reactions are rare but have been reported at a greater frequency with valdecoxib than with other selective COX-2 inhibitors (e.g., celecoxib). Discontinue valdecoxib at the first appearance of a rash or any other manifestation of hypersensitivity./HUMAN EXPOSURE STUDIES/ Risk of potentially fatal GI ulceration, bleeding, and perforation. Most studies indicate less risk of GI ulceration than prototypical /SRP: NSAIDs/however, the relative risk remains to be established. Use with caution in patients at risk for GI bleeding (e.g., history of GI bleeding or ulceration, treatment with oral corticosteroids or anticoagulants, longer duration of /SRP: NSAID/ therapy, geriatric patients, debilitation, smokers, or alcohol dependence). Consider alternative therapy in those at high risk for GI bleeding. .../HUMAN EXPOSURE STUDIES/ Severe (rarely fatal) anaphylactoid reactions have occurred in patients receiving /SRP: NSAIDs/, and anaphylactoid reactions (e.g., anaphylaxis, angioedema) have been reported during postmarketing surveillance of valdecoxib. Such reactions occurred in patients with or without a history of allergic-type reactions to sulfonamides. ...Cross-sensitivity between aspirin and other /SRP: NSAIDs/ may occur. Do not use in patients with bronchospastic aspirin sensitivity. Avoid use in patients with aspirin triad. Caution in patients with preexisting asthma, as bronchospasms may occur. |
| Artificial Pollution Sources | Valdecoxib's production and use as an anti-inflammatory(1) may result in its release to the environment through various waste streams(SRC). |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)ValdecoxibvLess-DILI-concern3Warnings & precautionsDOI:10.1016/j.drudis.2016.02.015 |
| Environmental Bioconcentration | An estimated BCF of 23 was calculated for valdecoxib(SRC), using an estimated log Kow of 2.67(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. |
| Volatilization from Water/Soil | The Henry's Law constant for valdecoxib is estimated as 2.2X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that valdecoxib is expected to be essentially nonvolatile from water surfaces(2). Valdecoxib's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Valdecoxib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-10 mm Hg(SRC), determined from a fragment constant method(3). |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Valdecoxib was not carcinogenic in rats given oral doses up to 7.5 mg/kg/day for males and 1.5 mg/kg/day for females or in mice given oral doses up to 25 mg/kg/day for males and 50 mg/kg/day for females for two years./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Valdecoxib did not impair male rat fertility at oral doses up to 9.0 mg/kg/day./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In female rats, a decrease in ovulation with increased pre- and post-implantation loss resulted in decreased live embryos/fetuses at doses > or = 2 mg/kg/day. The effects on female fertility were reversible. This effects is expected with inhibition of prostaglandin synthesis and is not the result of irreversible alteration of female reproductive function./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The incidence of fetuses with skeletal anomalies such as semi-bipartite thoracic vertebra centra and fused sternebrae was slightly higher in rabbits at the oral dose of 40 mg/kg/day throughout organogenesis. Valdecoxib was not teratogenic in rabbits up to an oral dose of 10 mg/kg/day./GENOTOXICITY/ In animal studies valdecoxib was not mutagenic in the Ames test or a mutation assay in Chinese hamster ovary (CHO) cells. No clastogenic effect was observed in the chromosome aberration assay in CHO cells or in in vivo micronucleus test in rat bone marrow. |
| Environmental Abiotic Degradation | Valdecoxib is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(1). |
| Probable Routes of Human Exposure | Occupational exposure to valdecoxib may occur through inhalation and dermal contact with this compound at workplaces where valdecoxib is produced or used. The general population is exposed via ingestion of valdecoxib by its use as a drug. (SRC) |
| Environmental Fate/Exposure Summary | Valdecoxib's production and use as an anti-inflammatory may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 4.6X10-10 mm Hg at 25 °C indicates valdecoxib will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase valdecoxib will be removed from the atmosphere by wet and dry deposition. If released to soil, valdecoxib is expected to have no mobility based upon an estimated Koc of 190,000. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.2X10-11 atm-cu m/mole. Valdecoxib is not expected to volatilize from dry soil surfaces based upon its vapor pressure. If released into water, valdecoxib is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 23 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to valdecoxib may occur through inhalation and dermal contact with this compound at workplaces where valdecoxib is produced or used. The general population is exposed via ingestion of valdecoxib by its use as a drug. (SRC) |
| Water hazard class (WGK) | 3 |
| UN transport number | UN 3077 9 / PGIII |
| Risk statements (R) | 63-48/22-51/53 |
| Signal word | Warning |
| GHS pictogram | GHS08,GHS09 |
| Hazard symbols | Xn,N |
| Safety statements (S) | 36/37-61 |
| Storage class | 11 - Combustible Solids |
| GHS hazard statements | H361d-H373-H410 |
| Hazard class | Aquatic Chronic 1Repr. 2STOT RE 2 |
| GHS precautionary statements | P201-P202-P260-P273-P280-P308+P313 |
| Hazardous substances data | 181695-72-7(Hazardous Substances Data) |
Applications & Uses
Description
Valdecoxib is a second-generation COX-2 inhibitor, developed as a follow-up to celecoxib for the oral once-daily treatment of osteoarthritis, adult rheumatoid arthritis and menstrual pain. Valdecoxib is approximately 28,000-fold more selective against human recombinant COX-2 than human recombinant COX-1. In an ex viva human whole blood assay, the I&O values against COX-2 and COX-1 were respectively 0.89 PM and 25.4 FM. In animal models, valdecoxib possesses excellent oral activity as an antiinflammatory. In rats, valdecoxib potently inhibited carrageenan footpad edema and adjuvant-induced arthritis.
Uses
Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in animal models. It is a potent and selective inhibitor of prostaglandin synthesis primarily through inhibition of COX-2. Valdecoxib is used to relieve some symptoms caused by arthritis (rheumatism), such as inflammation, swelling, stiffness, and joint pain.
General Description
Valdecoxib (VCX) is a diaryl substituted isoxazole compound. It comprises of sulfonyl propanamide and is a metabolite of parecoxib.
Preparation & Synthesis
Preparation
The step for the synthesis of valdecoxib: Deoxybenzoin is converted to the corresponding oxime by treatment with hydroxylamine under basic conditions with sodium acetate in aqueous ethanol or in toluene in presence of potassium hydroxide in absolute ethanol. The treatment of the oxime under nitrogen with two equivalents of butyllithium in tetrahydrofuran is followed by cyclization in ethyl acetate or acetic anhydride to the isoxazoline derivative. Finally, treatment of the isoxazoline with cold chlorosulfuric acid followed by reaction of the intermediate with aqueous ammonia afforded valdecoxib.