144689-63-4 Usage
Description
Olmesartan medoxomil, also known as Benicar, is a synthetic imidazole derivative prodrug with antihypertensive properties. It is an angiotensin II receptor antagonist used to treat high blood pressure. Upon hydrolysis, olmesartan medoxomil is converted to olmesartan, which selectively binds to the angiotensin type 1 (AT1) receptor of angiotensin II in vascular smooth muscle and adrenal gland, thereby competing with angiotensin II binding to the receptor. This prevents angiotensin II-induced vasoconstriction and decreases aldosterone production, thereby preventing aldosterone-stimulated sodium retention and potassium excretion. Olmesartan medoxomil is a white to off-white crystalline powder and is well-tolerated with an excellent safety profile.
Uses
Used in Pharmaceutical Industry:
Olmesartan medoxomil is used as an antihypertensive agent for the treatment of high blood pressure. It works by blocking the binding of angiotensin II to the AT1 receptors in vascular muscle, preventing angiotensin II-induced vasoconstriction and decreasing aldosterone production. This leads to a reduction in blood pressure and provides 24-hour blood pressure control with once-daily dosing.
Additionally, olmesartan medoxomil has been shown to be effective in reducing blood pressure more significantly than other angiotensin II receptor antagonists at their recommended doses, making it a preferred choice for patients with essential hypertension.
Olmesartan medoxomil is also used as a pro-drug that is de-esterified to the active metabolite, olmesartan. It has a dual method of elimination, with about 60% eliminated by the liver and the remainder by the kidney. This feature allows for alternative excretion pathways to compensate in cases of impaired renal or hepatic function. Furthermore, olmesartan is not metabolized by the cytochrome P450 enzyme system, resulting in a low potential for metabolic drug interactions, which is particularly important when treating patients on multiple drug regimens, such as the elderly.
Originator
Sanky (Japan)
Biochem/physiol Actions
Olmesartan medoxomil is a selective Angiotensin II Type I receptor blocker and antihypertensive drug. Olmesartan medoxomil is converted enzymatically to the active form olmesartan.
Clinical Use
Angiotensin-II receptor antagonist:
Hypertension
Side effects
Dizziness or lightheadedness may occur as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.
Synthesis
Olmesartan Medoxomil can be synthesized in 8 steps from diaminomaleonitrile by successive reactions with trialkylorthopropanoate to access 2-propyl-imidazole-45dicarbonitrile, conversion of the two nitrile functions to the corresponding ethyl esters, followed by methylmagnesium bromide addition to give the corresponding 4-(1-hydroxyalkyl)imidazole derivative. The imidazole ring of olmesartan (18) was constructed with diaminomaleonitrile 155 and trimethylorthobutyrate (156) in CH3CN then xylene to give 157 in 96% yield. Acid hydrolysis of 157 in 6N HCl gave the dicarboxylic acid intermediate. After esterification of the diacid in ethanol in the presence of HCl, diester 158 was treated with MeMgCl to give 4-(1-hydroxyalkyl) imidazole 159 in 95% yield. Alkylation of 159 with biphenyl bromide 160 in the presence of potassium tbutoxide afforded 161 in 80% yield. Ester 161 was then hydrolyzed to free carboxylic acid 162 under basic conditions, and 162 was treated with chloride 163 in the presence of K2CO3 to give ester 164 in 88% yield from 161.Lastly, the trityl group was removed with 25% aqueous acetic acid to give olmesartan (18) in 81% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: antagonism of hypotensive effect and
increased risk of renal impairment with NSAIDs;
hyperkalaemia with ketorolac and other NSAIDs.
Antihypertensives: increased risk of hyperkalaemia
hypotension and renal impairment with ACE-Is and
aliskiren.
Ciclosporin: increased risk of hyperkalaemia and
nephrotoxicity.
Diuretics: enhanced hypotensive effect;
hyperkalaemia with potassium-sparing diuretics.
ESAs: increased risk of hyperkalaemia; antagonism
of hypotensive effect.
Lithium: reduced excretion (possibility of enhanced
lithium toxicity).
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia and
nephrotoxicity.
Metabolism
Olmesartan medoxomil is an ester prodrug that is
hydrolysed during absorption from the gastrointestinal
tract to the active form olmesartan.
It is excreted in the urine and the bile as olmesartan;
about 35-50% of the absorbed dose is excreted in the
urine and the remainder in the bile.
Check Digit Verification of cas no
The CAS Registry Mumber 144689-63-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,4,6,8 and 9 respectively; the second part has 2 digits, 6 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 144689-63:
(8*1)+(7*4)+(6*4)+(5*6)+(4*8)+(3*9)+(2*6)+(1*3)=164
164 % 10 = 4
So 144689-63-4 is a valid CAS Registry Number.
144689-63-4Relevant articles and documents
Understanding and Controlling the Formation of an N-Alkyl Impurity in Olmesartan Medoxomil: A Derivative via Michael-Type Addition between Tetrazole and Mesityl Oxide in Situ Generated from Acetone
Lu, Jianwu,Shi, Yinfei,Li, Xiao,Liang, Xiaomin,Wang, Yinquan,Yuan, Shun,Wu, Taizhi
, p. 1112 - 1122 (2021)
An unknown impurity was detected in olmesartan medoxomil active pharmaceutical ingredient (API), which was determined as 2-methyl-4-oxopentan-2-yl-protected olmesartan medoxomil by NMR and mass spectrometry (MS). The formation mechanism of this impurity was investigated. In summary, the tetrazole of the final product was condensed with the potential genotoxic compound mesityl oxide generated from acetone self-condensation in acidic conditions to form the N-Alkyl impurity. Further quality control of the reaction was investigated using statistical methods (design of experiment, DoE) via a definitive screening design. The key factors of the reaction were determined to control the process parameters. Three batches of validation experiments showed that the generation of the N-Alkyl impurity was suppressed (0.1%) and the residual mesityl oxide was not detected (2.5 ppm).
Preparation method of high purity olmesartan medoxomi I
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Paragraph 0015; 0035; 0036; 0038, (2018/09/08)
The invention relates to a preparation method of high purity olmesartan medoxomi I. The preparation method comprises following steps: 1,5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole (A) and ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (B) are taken as raw materials to prepare an olmesartan medoxomi I intermediate 1 (C) through condensation reaction; theolmesartan medoxomi I intermediate 1 (C) is subjected to hydrolysis in the presence of sodium hydroxide so as to obtain a compound (D); without separation, the compound (D) and raw material 4-Cloromethyl-5-methyl-1,3-dioxol-2-one (E) are directly subjected to condensation reaction so as to obtain an olmesartan medoxomi I intermediate 2 (F); and the olmesartan medoxomi I intermediate 2 (F) is subjected to deprotection in a 75% acetic acid aqueous solution so as to obtain olmesartan medoxomi I crude product, and acetone is adopted for recrystallization so as to obtain high purity olmesartan medoxomi I (G). The reaction conditions are mild; side products are few; the finished product purity is high; the preparation method is safe, is friendly to the environment, and is suitable for industrialized production; residual solvent is less; and quality standards are achieved.
Production of [orumesarutanmedokisomiru[orumesarutanmedokisomiru]
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Paragraph 0042, (2017/05/23)
PROBLEM TO BE SOLVED: To provide a method for easily producing a crystal of a high-purity (5-methyl-2-oxo-1,3-dioxolene-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-tetrazole-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate in which the content of low polar impurities derived from olmesartan is reduced.SOLUTION: There is provided a method of carrying out a deprotection reaction of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trimethyltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid(5-methyl-2-oxo-1,3-dioxolene-4-yl)methylester in an acid aqueous solution having a pKa of 2.5 to 6.0 at a temperature of 30 to 45°C.