Ezetimibe CAS 163222-33-1

Introduction：Basic information about Ezetimibe CAS 163222-33-1, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Ezetimibe Basic information

• Product Name: Ezetimibe
• Synonyms: (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one;Ezetimibe-001;Ticagrelor and its interMediate;Ezetimibe 1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxy-propyl]-4-(4-hydroxyphenyl)-azetidin-2-one;Ezatimibe;zetia/vytorin;SCH 60969;Ezetimibe, >=99%
• CAS: 163222-33-1
• MF: C24H21F2NO3
• MW: 409.43
• EINECS: 682-606-0
• Product Categories: Isotope;CEDAX;Final material;API;Ezetimibe;Cardiovascular APIs;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;163222-33-1
• Mol File: 163222-33-1.mol

Ezetimibe Chemical Properties

• Melting point: 164-166°C
• alpha: D22 -33.9° (c = 3 in methanol)
• Boiling point: 654.9±55.0 °C(Predicted)
• density: 1.334±0.06 g/cm3(Predicted)
• storage temp.: 2-8°C
• solubility: Soluble in DMSO (up to 25 mg/ml) or in Ethanol (up to 15 mg/ml)
• pka: 9.72±0.30(Predicted)
• form: powder
• color: White or off-white
• Optical Rotation: -28.9314°(C=1.0022g/100ml MEOH)
• BCS Class: 2
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
• InChI: InChI=1S/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
• InChIKey: OLNTVTPDXPETLC-XPWALMASSA-N
• SMILES: N1(C2=CC=C(F)C=C2)[C@H](C2=CC=C(O)C=C2)[C@@H](CC[C@@H](C2=CC=C(F)C=C2)O)C1=O
• CAS DataBase Reference: 163222-33-1(CAS DataBase Reference)
• EPA Substance Registry System: 2-Azetidinone, 1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-, (3R,4S)- (163222-33-1)

Safety Information

• Risk Statements: 36/37/38
• Safety Statements: 26-36-24/25
• RIDADR: UN3077
• WGK Germany: WGK 3
• RTECS: CM4554000
• HazardClass: 9
• HS Code: 29337900
• Storage Class: 11 - Combustible Solids
• Hazardous Substances Data: 163222-33-1(Hazardous Substances Data)

Ezetimibe Usage And Synthesis

Description

Ezetimibe is ananti-hyperlipidemic drug used for lowering the plasma cholesterol levels. It is indicated as an adjunctive therapy to diet for the reduction of high-level total-C, LDL-C, and ApoB in patients suffering primary (heterozygous familial and non-familial) hypercholesterolemia. It is also used in combination therapy with HMG-CoA reductase inhibitors.Ezetimibe does not inhibit the cholesterol synthesis in the liver, or increase bile acid excretion.It takes effect throughacting at the brush border of the small intestine and inhibiting the absorption of cholesterol, further leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of blood cholesterol.

Indications and Usage

Ezetimibe is a new form of selective cholesterol absorption inhibitor developed in a collaboration between Schering-Plough Co. and Merck Co. This drug is the first cholesterol absorption selective inhibitor to be approved for sale by the American FDA. Its commercial name is Ezetrol.
This drug can be used alone or in combination with HMG-CoA reductase inhibitors (statins) to treat primary (heterozygous familial and non-familial) hypercholesterolemia, homozygous familial hypercholesterolemia (HoFH), homozygous viremia (or phytosterolemia).

Mechanisms of Action

Ezetimibe’s mechanisms of action are different from those of other lipid-lowering drugs (such as statins, cholic acid chelating agents, phenoxy acid derivatives, and plant sterols). This drug binds with the surface proteins on the brush border membrane vesicles of the small intestine (relative molecular mass 145x10^3) to inhibit the small intestine’s absorption of cholesterol in food and bile, thus decreasing the cholesterol content in serum and the liver. Ezetimibe is different from bile acid sequestrants because it does not affect the absorption of cholesterol esters, other steroids (such as bezoar and cholic acid), three triacylglycerol, and fat-soluble vitamins. Its effects are unrelated to whether or not acetyl coenzyme A- cholesterol acetyltransferase (ACAT) is inhibited or whether or not the LDL receptor (scavenger receptor) is expressed. After Ezetimibe is absorbed and binds with glucuronic acid in the liver, it undergoes enterohepatic circulation and almost exclusively targets small intestine mucosa cells.

References

https://en.wikipedia.org/wiki/Ezetimibe
https://pubchem.ncbi.nlm.nih.gov/compound/Ezetimibe#section=Top
https://www.drugbank.ca/drugs/DB00973
Davidson, Michael H, et al. "Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia ☆." Journal of the American College of Cardiology 40.12(2002):2125.
Sudhop, T, et al. "Inhibition of intestinal cholesterol absorption by ezetimibe in humans. " Circulation 106.15(2002):1943-8.

Description

Ezetimibe is a once-daily orally active cholesterol absorption inhibitor, launched as ahypolipidemic agent. The one-step diastereo- and enantioselective formation of β-lactamsstarting from commercially available (3S)-hydroxy-y-lactone is the key point of theasymmetric synthesis of ezetimibe. The 2-azetidinone class was initially designed as acylcoenzymeA: cholesterol acyltransferase (ACAT) inhibitors but experimental data suggestthat this compound acts in the intestinal wall to inhibit cholesterol through a novelmechanism with an as yet undiscovered target. Orally administered ezetimibe inhibitedincreases in plasma cholesterol in four cholesterol-fed animals species (hamster, rats,dogs and rhesus monkeys). In rats cannulated in the intestine and bile duct, [³H]-ezetimibeinhibited cholesterol absorption by more than 95%. In cholesterol-fed LDL receptor+apoEknockout mice, treatment with ezetimibe reduced atherosclerotic lesion cross sectionalarea by 48% in the aorta and 20% in the carotid artery. Moreover, the plasma cholesterollevels were reduced and the progression of lesions was inhibited. Ezetimibe is highlyprotein bound and is metabolized by the liver to its glucuronide metabolite, whichrepresents 80-90% of circulating ezetimibe. About 90% of ezetimibe and/or theglucuronide metabolite are excreted in the feces and 10% in the urine. The parentcompound and its glucuronide metabolite undergo enterohepatic recirculation; inconsequence, the drug is slowly eliminated. In hypercholesterolemic patients, ezetimibe(10 mglday, 12 weeks) reduced LDL cholesterol by 18% and total cholesterol by 12%, witha similar safety profile to placebo. Co-administration of ezetimibe with statins or fenofibratelowered LDL cholesterol levels more than either monotherapy. Ezetimibe was welltolerated and interaction studies provided evidence that ezetimibe had no significant effecton the activity of major CYP450 drug-metabolizing enzymes. Moreover, nopharmacokinetic/pharmacodynamic interactions were seen between ezetimibe and statinsand others frequently administered drugs..

Chemical Properties

White Solid

Originator

Schering-Plough (USA)

History

Ezetimibe (brand name Zetia) was approved by the FDA in October 2002 for lowering levels of total cholesterol and LDL (bad) cholesterol in the blood. Zetia is used to treat high cholesterol in people whose cholesterol levels cannot be controlled by diet and exercise alone. It is sometimes given in combination with other cholesterol-lowering drugs, including fenofibrate, or statins, such as atorvastatin, lovastatin, simvastatin, pravastatin, or fluvastatin.

Uses

antibacterial

Uses

A cholesterol transport inhibitor that binds to NPC1L1

Uses

For use as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia.

Uses

Ezetimibe (9) was approved as the first hypolipidemicdrug to act by blocking the absorption of dietary cholesterol.This drug was discovered by Schering-Plough and is codevelopedand co-marketed by Merck and Schering-Ploughfor the treatment of hypercholesterolemia and also two lesscommon forms of hyperlipidemia: homozygous familialhypercholesterolemia and homozygous sitosterolemia.

Definition

ChEBI: Ezetimibe is a beta-lactam that is azetidin-2-one which is substituted at 1, 3, and 4 by p-fluorophenyl, 3-(p-fluorophenyl)-3-hydroxypropyl, and 4-hydroxyphenyl groups, respectively (the 3R,3'S,4S enantiomer). It has a role as an anticholesteremic drug, an antilipemic drug and an antimetabolite. It is a member of azetidines, an organofluorine compound and a beta-lactam.

Brand name

Zetia (Merck/Schering-Pough);Ezetrol.

Biological Functions

Ezetimibe lowers plasma cholesterol levels by inhibiting the absorption of cholesterol at the brush border of the small intestine.Specifically, it has been proposed to bind to a specific transport protein located in the wall of the small intestine, resulting in a reductionof cholesterol transport and absorption. Ezetimibe appears to be selective in its actions in that it does not interfere with theabsorption of triglycerides, lipid-soluble vitamins or other nutrients. The decreased absorption of cholesterol eventually leads to enhanced receptor-mediated LDL uptake similar to that seen with bile acid sequestrants and HMGRIs. When used asmonotherapy, the decreased absorption of cholesterol causes a compensatory increase in cholesterol biosynthesis. This is similar tothat described for bile acid sequestrants and is insufficient to override the overall LDL lowering effects of ezetimibe.

General Description

Ezetimibe, (3R,4S)-1-(4-fluorophenyl)-3-((3S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)-2-azetidinone (Zetia), is an antihyperlipidemicagent that has usefulness in lowering cholesterol levels. Itacts by decreasing cholesterol absorption in the intestine byblocking the absorption of the sterol at the Brush boarder.Specifically, the -lactam binds to the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract that isresponsible for cholesterol absorption. Although it may beused alone, it is marketed as a combination product withsimvastatin under the trade name Vytorin.

Biochem/physiol Actions

Ezetimibe is a non statin drug that reduces intestinal cholesterol absorption. In addition, it also has an ability to reduce the risk of cardiovascular events in patients who had had an acute coronary syndrome and whose low-density lipoprotein (LDL) cholesterol values were within guideline recommendations.

Pharmacokinetics

Ezetimibe is administered orally; however, its absolute bioavailability cannot be determined because of its aqueous insolubility and thelack of an injectable formulation. Based on area under the curve values, the oral absorption ranges from 35 to 60%. Mean peakconcentrations of the active glucuronidated metabolite are reached within 1 to 2 hours. Both ezetimibe and its glucuronide conjugate areextensively bound (>90%) to plasma proteins. The relative plasma concentrations of ezetimibe and its glucuronide conjugate range from10 to 20% and from 80 to 90%, respectively. Both compounds have a long half-life of approximately 22 hours. The coadministration offood with ezetimibe has no effect on the extent of absorption.

Clinical Use

Ezetimibe is indicated as monotherapy or in combination with an HMGRI for the reduction of elevated total cholesterol, LDL cholesterol,and apoB in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia. When used as monotherapy, ezetimibereduces LDL cholesterol by approximately 18%. When used in combination therapy with an HMGRI, LDL levels are reduced by 25 to 65%depending on the dose of the HMGRI inhibitor. Ezetimibe also is indicated for homozygous familial hypercholesterolemia in combinationwith either atorvastatin or simvastatin and for homozygous familial sitosterolemia. All indications are for patients who have notresponded to diet, exercise, and other nonpharmacological methods.

Side effects

Ezetimibe generally is well tolerated. The most common adverse effects are listed above. Whenever ezetimibe is used in combinationwith an HMGRI, the incidence of myopathy or rhabdomyolysis does not increase above that seen with HMGRI monotherapy.

Synthesis

The synthesis of ezetimibe (9) begins with the one-stepdiastereoselective and practical synthesis of the trans |?-lactam from commercially available (S)-3-hydroxy-|?-lactone(92). Lactam 95 was obtained by generation of a dianion oflactone 92 with LDA in THF followed by addition of theimine and N,N?ˉ-dimethylpropyleneurea (DMPU) to givepredominately adduct 93 (93:94 = 79:21). However,intermediate 93 and 94 did not cyclize to their respectivelactams due to formation of stable lithium aggregates.Addition of lithium chloride/DMF was employed to cyclizethe intermediates into trans-lactam 95 as the major product(trans:cis = 95:5) in a one-pot process from 92 in 64%yield. The 95:5 ratio of compound 95 was oxidativelycleaved with NaIO4 to give aldehyde 96. Mukaiyama aldolcondensation was adopted to elaborate the 4-fluorophenylpropylside chain to give alcohol 98. Withoutisolation, the reaction mixture was subjected to dehydrationusing p-TSA to give enone 99 in 75% yield from compound96. Reduction of the double bond in 99 with Wilkinson?ˉscatalyst yielded ketone 100, which was subjected to thehighly enantioselective CBS reduction to give alcohol 101with a 98:2 selectivity of S:R at the benzylic position.Catalytic hydrogenation of compound 101 gave ezetimibe(9) in 79% yield. Alternatively, a palladium-catalyzeddouble reduction in EtOAc/MeOH of both the double bondand the benzyl protecting group in enone 99 produced freephenol 107 in 90% yield. A three-step one-pot procedurewas subsequently developed to transform 107 into ezetimibe(9) in 79% yield. That is, free phenol 107 was protected insitu as its TMS ether using BSU followed by a highlyselective CBS reduction of the ketone group to give the desired alcohol in 97% ee. The TMS group was removedduring acidic workup to give ezetimibe (9). A moreconvergent approach to this drug was also developed bypreparing the (S)-hydroxy side chain before the ringconstruction. Therefore, p-fluorobenzoylbutyric acid(102) was reacted with pivaloyl chloride and the acidchloride thus obtained was acylated with chiral auxiliary 103to give the corresponding amide. The ketone group in theamide was reduced with (R)-MeCBS/BH3-THF (104) in thepresence of p-TSA to give desired alcohol 105 in high yield(99%) and stereoselectivity (96 % d.e.). Chiral alcohol105 was then mixed with the imine in the presence ofTMSCl and DIPEA to protect the alcohols as TMS ethers.In the same pot, TiCl4 was added to catalyze thecondensation reaction and gave compound 106 in 65% yield.Compound 106 was reacted with TBAF and a fluoridecatalyzedcyclization took place to give the correspondinglactam. Finally, the TMS protecting group was removedunder acidic conditions to give ezetimibe (9) in 91% yieldover two steps.

target

MEK | ERK

Drug interactions

Potentially hazardous interactions with other drugs
Ciclosporin: concentration of both drugs possibly increased.
Lipid lowering agents: avoid with fibrates; concentration of rosuvastatin increased - reduce rosuvastatin dose.

Metabolism

Following oral administration, ezetimibe is rapidly and extensively metabolized in the intestinal wall and the liver to its active metabolite,a corresponding phenol glucuronide. This glucuronide is reexcreted in the bile back to its active site. A small amount (<5%) of ezetimibeundergoes oxidation to covert the benzylic hydroxyl group to a ketone; however, ezetimibe does not appear to exert any significant effecton the activity of CYP450 enzymes.

References

[1] WANG D Q H. Regulation of intestinal cholesterol absorption.[J]. Annual review of physiology, 2007, 69: 221-248. DOI:10.1146/annurev.physiol.69.031905.160725
[2] MARGARITA GARCIA-CALVO. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).[J]. Proceedings of the National Academy of Sciences of the United States of America, 2005: 8132-8137. DOI:10.1073/pnas.0500269102
[3] JUAN FIDEL OSUNA-RAMOS. Ezetimibe inhibits dengue virus infection in Huh-7 cells by blocking the cholesterol transporter Niemann–Pick C1-like 1 receptor[J]. Antiviral research, 2018, 160: Pages 151-164. DOI:10.1016/j.antiviral.2018.10.024
[4] SOO HYUN KIM. Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition.[J]. Autophagy, 2017, 13 10: 1767-1781. DOI:10.1080/15548627.2017.1356977

Ezetimibe Preparation Products And Raw materials

• Raw materials: (3'R)-Ezetimibe-->EZM-K-->(3R,4S)-4-(4-(Benzyloxy)Phenyl)-1-(4-Fluorophenyl)-3-((S)-3-(4- Fluorophenyl)-3-Hydroxypropyl)Azetidin-2-One-->(3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one