HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Irbesartan
AVAPRO · Lrbesartan · Irbesatan · Irbersartan · Irbesartan Impurity 1 · 3-butyl-2-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-2,4-diazaspiro[4.4]non-3-en-1-one · CS-1097 · APROVEL
Identifikatoren & physikalische Daten
| CAS No. | 138402-11-6 |
|---|---|
| Summenformel | C25H28N6O |
| Durchschnittliche Molmasse | 428,5 g/mol |
| Monoisotopische Masse | 428,23245954 g/mol |
| SMILES | CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1 |
| InChIKey | YOSHYTLCDANDAN-UHFFFAOYSA-N |
| PubChem CID | 3749 |
| ChEMBL | CHEMBL1513 |
| ChEBI | CHEBI:5959 |
| EC No. | 604-078-2 |
| DTXSID | DTXSID0023169 |
Chemische & physikalische Eigenschaften
| XLogP | 4,1 |
|---|---|
| Polarare Oberfläche (TPSA) | 87,1 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 5 |
| Frei drehbare Bindungen | 7 |
| Schwere Atome | 32 |
| Formalladung | 0 |
| Komplexität | 682 |
| LogP (Verteilungskoeffizient) | 4.56 |
| Color/Form | Crystals from 96% ethanol |
| Löslichkeit | <1mg/mLPractically insoluble in waterSlightly soluble in alcohol, methylene chloride8.84e-03 g/LDMSO: >25mg/mL |
| Siedepunkt | 648.6648.6±65.0 °C(Predicted) |
| Decomposition | Hazardous decomposition products: Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx). |
| Schmelzpunkt | 180-181 °C180 - 181 °C180-181°C |
| Physical Description | Solid |
| Stability/Shelf Life | Stable under recommended storage conditions. |
| Collision Cross Section | 214.1 Ų [M+K]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]199.87 Ų [M+H]+ [CCS Type: TW212.33 Ų [M+Na]+ [CCS Type: TW186.9 Ų [M+H-H2O]+ [CCS Type: TW200.8 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]201.2 Ų [M+H]+ [CCS Type: TW214.21 Ų [M-H]-202.81 Ų [M+H]+ |
| Dichte | 1.30±0.1 g/cm3(Predicted) |
| Lagerbedingungen | 2-8°C |
| pKa (Säurekonstante) | 4.16±0.10(Predicted) |
| Aggregatzustand | powder |
| Farbe | white to off-white |
| Merck | 14,5083 |
| BCS Class | 2 |
| InChIKey | YOSHYTLCDANDAN-UHFFFAOYSA-N |
| SMILES | N1C2(CCCC2)C(=O)N(CC2=CC=C(C3=CC=CC=C3C3=NNN=N3)C=C2)C=1CCCC |
| CAS Datenbank | 138402-11-6(CAS DataBase Reference) |
| EPA chemische Informationen | 1,3-Diazaspiro[4.4]non-1-en-4-one, 2-butyl-3-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- (138402-11-6) |
Sicherheit & Vorschriften
| GHS-Einstufung | This chemical does not meet GHS hazard criteria for 1% (1 of 104) of reports.DangerH315 (57.7%): Causes skin irritation [Warning Skin corrosion/irritation]H319 (56.7%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]H335 (56.7%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposureRespiratory tract irritation]H360 (24%): May damage fertility or the unborn child [Danger Reproductive toxicity]H361 (17.3%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]H362 (18.3%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]H372 (14.4%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]H412 (15.4%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]P203, P260, P261, P263, P264, P264+P265, P270, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 104 reports by companies from 19 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Reported as not meeting GHS hazard criteria per 1 of 104 reports by companies.There are 18 notifications provided by 103 of 104 reports by companies with hazard statement code(s).Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website. |
|---|---|
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including irbesartan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Hazard Classes and Categories | Skin Irrit. 2 (57.7%)Eye Irrit. 2 (56.7%)STOT SE 3 (56.7%)Repr. 1B (24%)Repr. 2 (17.3%)Lact. (18.3%)STOT RE 1 (14.4%)Aquatic Chronic 3 (15.4%) |
| Hazardous Reactivities and Incompatibilities | Incompatible materials: Strong oxidizing agents. |
| Brandbekämpfungsverfahren | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. |
| Lagerbedingungen | Store at 25 °C (77 °F)excursions permitted to 15-30 °C (59-86 °F).Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 °C. |
| Reinigungsverfahren | Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.Waste treatment methods. Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. |
| Preventive Measures | Precautions for safe handling: Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker. |
| Personal Protective Equipment (PPE) | Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).Skin protection: Handle with gloves.Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). |
| Wechselwirkungen | Do not coadminister aliskiren with Avapro in patients with diabetes. Avoid use of aliskiren with AVAPRO in patients with renal impairment (GFR <60 mL/min).Dual blockade of the renin-angiotensin system (RAS) with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Avapro and other agents that affect the RAS.Concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.Possible decreased irbesartan metabolism when irbesartan is used concomitantly with tolbutamide.For more Interactions (Complete) data for Irbesartan (6 total), please visit the HSDB record page. |
| Hepatotoxicity | Irbesartan has been associated with a low rate of serum aminotransferase elevations (Likelihood score: C (Probable rare cause of clinically apparent liver injury). |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+6(SRC), determined from a structure estimation method(2), indicates that irbesartan is expected to be immobile in soil(SRC). The estimated pKa values of irbesartan are 4.08 and 4.29(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of ibesartan from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.0X10-15 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Irbesartan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2014).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+6(SRC), determined from a structure estimation method(2), indicates that irbesartan 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 5.0X10-15 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 1500(SRC), from its estimated log Kow(2)and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism(SRC). Biodegradation data in water were not available(SRC, 2014).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), irbesartan, which has an estimated vapor pressure of 1.2X10-15 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 irbesartan may be removed from the air by wet and dry deposition(SRC). Irbesartan contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). |
| Milk Concentrations | EXPERIMENTAL: It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in the milk of lactating rats. |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Irbesartan crystals are formulated into oral tablets. Irbesartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive drugs in the management of hypertension. It is also used for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension. HUMAN EXPOSURE AND TOXICITY: The most likely manifestations of irbesartan overdose include hypotension and tachycardiabradycardia might also occur from overdose. The use of irbesartan in pregnancy is contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension that are resistant to both pressor agents and volume expansion may occur in the newborn following in utero exposure to irbesartan. ANIMAL STUDIES: No evidence of carcinogenicity was observed when irbesartan was administered in rats or mice for up to 2 years. Also, the fertility or mating of male and female rats was unaffected by administration of irbesartan. When pregnant rats were treated with the drug from day 0 to day 20 of gestation, increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses as low as 50 mg/kg/day. Subcutaneous edema was observed in fetuses at doses as low as 180 mg/kg/day. As these anomalies were not observed in rats in which drug exposure was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of irbesartan can be estimated to be 1.3X10+6(SRC). According to a classification scheme(2), this estimated Koc value suggests that irbesartan is expected to be immobile in soil. The estimated pKa values of 4.08 and 4.29(3) indicate that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Irbesartan adsorption isotherms (Kd) of 7.0X10+2 L/kg and 9.4X10+2 L/kg were measured in primary sludge and long-age secondary sludge, respectively. Sludge was obtained from 2 wastewater treatment plants that were representative of plants utilized in industrialized countries(5). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ No data are available in regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks were well-tolerated. The most likely manifestations of overdosage are expected to be hypotension and tachycardiabradycardia might also occur from overdose./GENOTOXICITY/ IIrbesartan was negative in ... /the/ in vitro-human lymphocyte assay ... ./OTHER TOXICITY INFORMATION/ Drugs that act directly on the renin-angiotensin system (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters. ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Irbesartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy./OTHER TOXICITY INFORMATION/ The human pregnancy experience with irbesartan is limited. However, the antihypertensive mechanisms of action of irbesartan and angiotensin-converting enzyme (ACE) inhibitors are very close. That is, the former selectively blocks the binding of angiotensin II to AT1 receptors, whereas the latter prevents the formation of angiotensin II itself. Therefore, use of this drug during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity identical to that seen with ACE inhibitors. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension that are resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to irbesartan. Newborn function and blood pressure should be closely monitored./OTHER TOXICITY INFORMATION/ In July 2010, the US Food and Drug Administration (FDA) initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis suggested a possible association between the use of these agents and an increased risk of cancer. The meta-analysis, which combined cancer-related findings from 5 randomized, controlled trials in over 60,000 patients, found a modest but significant increase in the risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist (mostly telmisartan) compared with those in control groups (7.2 versus 6%, respectivelyrisk ratio 1.08). However, because of several limitations of the study (e.g., trials included in the meta-analysis were not specifically designed to evaluate cancer outcomes, lack of individual patient data), the validity of these findings has been questioned. Subsequent studies, including a larger, more comprehensive meta-analysis conducted by FDA, have not shown an increased risk of cancer in patients receiving angiotensin II receptor antagonists. FDA's meta-analysis, which included trial-level data from 31 randomized studies (total of approximately 156,000 patients), found no evidence of an increased risk of cancer in patients who received an angiotensin II receptor antagonist compared with those who received other treatments (placebo or active control). The overall rate of new cancer occurrence was essentially the same in both groups of patients (1.82 and 1.84 cases per 100 patient-years, respectively). In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups. Based on these results and a review of all currently available data related to this potential safety concern, FDA has concluded that use of angiotensin II receptor antagonists is not associated with an increased risk of cancer. |
| Artificial Pollution Sources | Irbesartan's production and administration as an antihypertensive(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)IrbesartanvLess-DILI-concern5Adverse reactionsDOI:10.1016/j.drudis.2016.02.015 |
| Environmental Bioconcentration | An estimated BCF of 1500 was calculated in fish for irbesartan(SRC), using an estimated log Kow of 5.31(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC). |
| Volatilization from Water/Soil | The Henry's Law constant for irbesartan is estimated as 7.0X10-15 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that irbesartan is expected to be essentially nonvolatile from water and moist soil surfaces(2). Irbesartan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-15 mm Hg(SRC), determined from a fragment constant method(3). |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average systemic exposure to irbesartan (AUC0-24 hour, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure in humans receiving the maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided an average systemic exposure about 21 times that reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses =50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at doses =180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses =650 mg/kg/day, the highest dose providing a systemic exposure to irbesartan (AUC0-24 hour, bound plus unbound) about 5 times that found in humans receiving the maximum recommended dose of 300 mg/day./GENOTOXICITY/ Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in ... the in vivo-mouse micronucleus study. |
| Wassergefährdungsklasse (WGK) | 3 |
| Zollcode | 29332900 |
| RTECS-Nr. | HM2950270 |
| R-Sätze (R) | 22 |
| Gefahrensymbole | Xn |
| Sicherheitshinweise (S) | 26-24/25 |
| Lagerklasse | 11 - Combustible Solids |
| Gefahrstoffdaten | 138402-11-6(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Avapro was launched in Germany, the UK and the US for hypertension. It can be prepared in six steps starting with cyclopentanone or in three steps from 1- aminocyclopentanecarboxylic acid ethyl ester and pentanimidic ethyl ester. Avapro is an angiotensin Ⅱ receptor antagonist that is non-competitive and selective for AT, subtypes and has no AT2 activity at postsynaptic receptors compared to presynatpic. It has no affinity for various non angiotensin Ⅱ receptor types in binding, no interaction with calcium channels or antiports, and no affinity for α1- and α2--adrenoreceptors, serotonergic receptors, muscarinic m1 and m2 or other receptors. It is as potent as saralasin but with no agonist activity and is 10 times more potent than DuP753 in rats. It is similar in efficacy to enalapril (in those with severe hypertension) and atenolol, while more effective than losartan for mild to moderate hypertension.
Verwenden
For the treatment of hypertension, as well as diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. Irbesartan is also used as a second line agent in the treatment of conges