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Your Location：Home>Product Center >> Pharmaceutical API >> Ezetimibe
  • Ezetimibe
Name:Ezetimibe
CAS No:163222-33-1

PRODUCT DESCRIPTION

  Ezetimibe  Intermediates click here

【Name】

Ezetimibe
【Iupac name】
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
【CAS Registry number】
163222-33-1
【Synonyms】
(-)-Sch 58235
Zetia (TN)
Zetia
Ezetimibe 1-(4-flurophenyl)-(3R)-[3-(4-flurophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone
2-Azetidinone,1-(4-fluorophenyl)-3-[(3S)-3- (4-fluorophenyl)-3-hydroxypropyl]-4-(4- hydroxyphenyl)-,(3R,4S)-
Sch 58235
Vytorin
Ezedoc
(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone
【Molecular Formula】
C24H21F2NO3 (Products with the same molecular formula)
【Molecular Weight】
409.43
【Inchi】
InChI=1/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1
【Canonical SMILES】
C1=CC(=CC=C1C2C(C(=O)N2C3=CC=C(C=C3)F)CCC(C4=CC=C(C=C4)F)O)O
【Isomers smiles】
C1=CC(=CC=C1[C@@H]2[C@H](C(=O)N2C3=CC=C(C=C3)F)CC[C@@H](C4=CC=C(C=C4)F)
O)O
【MOL File】
163222-33-1.mol

Chemical and Physical Properties

【Appearance】
white powder
【Density】
1.334g/cm3
【Melting Point】
164-166℃
【Boiling Point】
654.9°C at 760 mmHg
【Vapour】
4.83E-18mmHg at 25°C
【Refractive Index】
1.623
【Flash Point】
349.9°C
【Solubilities】
In water, 4.4 mg/L at 25 deg C (est)
【Color/Form】
White solid
【Spectral properties】
Specific optical rotation: -33.9 degrees at 22 deg C/D (c = 3 in methanol)
【Computed Properties】
Molecular Weight:409.425246 [g/mol]
Molecular Formula:C24H21F2NO3
XLogP3-AA:4
H-Bond Donor:2
H-Bond Acceptor:5
Rotatable Bond Count:6
Tautomer Count:4
Exact Mass:409.14895
MonoIsotopic Mass:409.14895
Topological Polar Surface Area:60.8
Heavy Atom Count:30
Formal Charge:0
Complexity:567
Isotope Atom Count:0
Defined Atom Stereocenter Count:3
Undefined Atom Stereocenter Count:0
Defined Bond Stereocenter Count:0
Undefined Bond Stereocenter Count:0
Covalently-Bonded Unit Count:1
Feature 3D Acceptor Count:2
Feature 3D Donor Count:2
Feature 3D Ring Count:4
Effective Rotor Count:6.6
Conformer Sampling RMSD:0.8
CID Conformer Count:21

Safety and Handling

【Risk Statements】
R36/37/38
【Safety Statements 】
S26
【Safety】
Risk Statements: 36/37/38
R36/37/38:Irritating to eyes, respiratory system and skin. 
Safety Statements: 26-36
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
S36:Wear suitable protective clothing. 
Use cautiously in:
1)breastfeeding patients
2)children younger than age 10
3)pregnant patients not receiving HMG-CoA reductase inhibitors
4)renal or hepatic impairment
5)elderly patients.
【Formulations/Preparations】
Oral: Tablets: 10 mg with Simvastatin 10 mg Vytorin (Merck/Schering-Plough); 10 mg with Simvastatin 20 mg Vytorin (Merck/Schering-Plough); 10 mg with Simvastatin 40 mg Vytorin (Merck/Schering-Plough); 10 mg with Simvastatin 80 mg Vytorin (Merck/Schering-Plough). /Ezetimibe combinations/
Oral: Tablets: 10 mg Zetia (Merck/Schering-Plough).
【Exposure Standards and Regulations】
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ezetimibe, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
【Specification】
Patient monitoring: 
1)Monitor hepatic and lipid profiles
2)Assess for and report unexplained muscle pain.
【Octanol/Water Partition Coefficient】
log Kow = 3.94 (est)
【Disposal Methods】

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Use and Manufacturing

【Use and Manufacturing】
Methods of Manufacturing
Preparation: S.B. Rosenblum et al., WO 9508532; eidem US 5767115 (1995, 1998 both to Schering)
【Usage】
Ezetimibe is an anti-hyperlipidemic medication which is used to lower Cholesterol levels. It acts by decreasing Cholesterol absorption in the intestine. It could be used alone when other Cholesterol-lowering medications are not tolerated, or when Cholesterol levels are unable to be controlled on statins alone, ezetimibe could be used together with statins

Biomedical Effects and Toxicity

【Pharmacological Action】
Substances used to lower plasma cholesterol levels.
【Therapeutic Uses】
Ezetimibe is used alone or in combination with other antilipemic agents (i.e., a hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor (statin), fenofibrate) as an adjunct to dietary therapy in the treatment of primary hypercholesterolemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, and/or homozygous familial sitosterolemia. /Included in US product label/
Ezetimibe is used alone or in combination with a statin as an adjunct to dietary therapy to decrease elevated serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B (apo B) concentrations in the treatment of primary (heterozygous familial and nonfamilial) hypercholesterolemia. Ezetimibe in fixed combination with simvastatin is used as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia. Ezetimibe also is used in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia. /Included in US product label/
Ezetimibe is used as an adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia. /Included in US product label/
Ezetimibe may be used in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available. /Included in US product label/
This is a retrospective review of all pediatric patients who received ezetimibe monotherapy as treatment for hypercholesterolemia and for whom follow-up clinical and lipid results were available. Of 36 identified patients, 26 had lipoprotein profiles suggestive of familial hypercholesterolemia (FH), and 10 had profiles suggestive of familial combined hyperlipidemia (FCHL). After a mean 105 days of treatment with ezetimibe (range, 32-175 days), total cholesterol (TC) levels decreased from 7.3 +/- 1.0 mmol/L to 5.7 +/- 1.0 mmol/L (P < .0001), and low-density lipoprotein cholesterol (LDL-C) levels decreased from 5.3 +/- 0.9 mmol/L to 3.9 +/- 0.8 (P < .0001) in patients with FH. In patients with FCHL, TC levels decreased from 6.4 +/- 2.0 mmol/L to 5.6 +/- 0.4 mmol/L (P < or = .002), and LDL-C levels decreased from 4.7 +/- 1.0 mmol/L to 3.8 +/- 0.6 mmol/L (P < or = .005). For all patients, the mean decrease in individual LDL-C values was 1.5 +/- 0.9 mmol/L or 28%. There was no significant change in triglyceride or high-density lipoprotein cholesterol levels with ezetimibe. Patients were maintained on ezetimibe with no adverse effects attributable to the medication for as long as 3.5 years. At a mean of 13.6 months (range, 1-44 months) after the initiation of ezetimibe, LDL-C levels remained decreased at 4.0 +/- 0.6 mmol/L. In this small retrospective series of children and adolescents with hypercholesterolemia, ezetimibe was safe and effective in lowering LDL-C levels. [Clauss S et al; J Pediatr 154 (6): 869-72 (2009). Available from, as of June 8, 2009:]
【Biomedical Effects and Toxicity】
Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. The drug and its active glucuronide metabolite impair the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol through inhibition of a membrane transporter yet to be identified. Absorption of ezetimibe is rapid and not altered by food content following oral administration. The drug is not metabolized by the cytochrome P450 system but extensive glucuronidation takes place in the intestine. Consequently, plasma concentrations of ezetimibe represent approximately 10% of total ezetimibe in plasma. Enterohepatic recirculation observed for ezetimibe and its glucuronimide significantly increases the residence time of these compounds in the intestine, at their site of action. Elimination of ezetimibe glucuronimide appears impaired in elderly patients and patients with renal insufficiency with plasma concentrations increased 1.5- to 2-fold. So far, no drug interaction study has been associated with major changes in either the pharmokinetics of ezetimibe or coadministered drugs. [Simard C, Turgeon J; Can J Clin Pharmacol 10 (Suppl A): 13A-20A (2003). Available from, as of June 2, 2009:] PubMed Abstract
Ezetimibe lowers plasma cholesterol levels by inhibiting the uptake of cholesterol in the intestine. Due to extensive enterohepatic circulation of ezetimibe, relative low doses are required to be effective. In blood and bile the majority of ezetimibe is present as a glucuronide-conjugate, which is formed in the enterocyte. Presently, it is not clear which mechanisms are responsible for this efficient enterohepatic circulation. Abcc2, Abcc3 and Abcg2 are ABC transporters, which are expressed in both liver and intestine and are capable of transporting glucuronidated compounds. The aim of this study was to investigate the contribution of these transporters in the enterohepatic cycling of ezetimibe-glucuronide (Ez-gluc). Transport studies were performed in plasma membrane vesicles from ABCC2, ABCC3 and ABCG2 expressing Sf21 insect cells. Furthermore, intestinal explants from wild-type and Abcc3-/- mice were used to study vectorial transport in an Ussing chamber setup. Finally, biliary excretion of Ez-gluc was measured in vivo after duodenal delivery of ezetimibe in wild-type, Abcc3-/-, Abcc2-/-, Abcg2-/- and Abcg2-/-/Abcc2-/- mice. ABCC3-, ABCC2- and ABCG2-mediated transport was dose dependently inhibited by Ez-gluc. In the Ussing chamber Ez-gluc recovered from the basolateral side was significantly reduced in duodenal (2.2%), in jejunal (23%) and in ileal (23%) tissue of Abcc3-/- compared to wild-type mice. Biliary excretion of Ez-gluc was significantly reduced in Abcc3-/- (34%), Abcc2-/- (56%) and Abcg2-/-/Abcc2-/- (2.5%) compared to wild-type mice. These data demonstrate that enterohepatic circulation of Ez-gluc strongly depends on the joint function of Abcc3, Abcc2 and Abcg2. [de Waart DR et al; Drug Metab Dispos. 2009 May 14. [Epub ahead of print]. Available from, as of June 1, 2009:] PubMed Abstract
It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma.
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Zetia to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.

Environmental Fate and Exposure Potential

【Environmental Fate/Exposure Summary】
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8.9X10+4(SRC), determined from a structure estimation method(2), indicates that ezetimibe is expected to be immobile in soil(SRC). The estimated pKa of ezetimibe is 9.7(3), indicating that this compound will partially exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of ezetimibe from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.4X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Ezetimibe is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.5X10-14 mm Hg at 25 deg C(SRC), determined from a fragment constant method(6). Biodegradation data were not available(SRC, 2009).
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8.9X10+4(SRC), determined from a structure estimation method(2), indicates that ezetimibe 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 4.4X10-18 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 109(SRC), from an estimated log Kow of 3.9(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Biodegradation data were not available(SRC, 2009).
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ezetimibe, which has an estimated vapor pressure of 1.5X10-14 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase ezetimibe may be removed from the air by wet or dry deposition(SRC). Ezetimibe does not contain chromophores that absorb at wavelengths >290 nm(3) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

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